View source for Fatal insomnia

{{Short description|Prion disease of the human brain}}
{{Use dmy dates|date=June 2018}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox medical condition (new)
| name = Fatal insomnia
| synonyms = 
| synonym = 
| image = 12883 2025 4315 Fig2 HTML.jpg
| alt = 
| caption = Longitudinal comparison of 18F-FDG PET/MRI in brain in a patient with fatal insomnia, demonstrating normal brain parenchyma on MRI, but prominent hypometabolism of the thalamus
| image_size = 300px
| pronounce = 
| field = [[Neurology]], [[psychiatry]], [[sleep medicine]], [[neuropathology]]
| symptoms = Progressive insomnia, ataxia, double vision, weight loss, high blood pressure, excessive sweating
| complications = Permanent state of [[hypnagogia]] later in the illness
| onset = 45–50 years old<ref>{{Cite web |title=Fatal Familial Insomnia |url=https://rarediseases.org/rare-diseases/fatal-familial-insomnia/ |access-date=2022-09-21 |website=NORD (National Organization for Rare Disorders) |language=en-US}}</ref>
| duration = 
| types = Fatal familial insomnia, sporadic fatal insomnia<ref name=Mer2019Pro>{{cite web |title=Fatal Insomnia – Neurologic Disorders |url=https://www.merckmanuals.com/en-ca/professional/neurologic-disorders/prion-diseases/fatal-insomnia |website=Merck Manuals Professional Edition |access-date=17 May 2019 |language=en-CA}}</ref>
| causes = [[Genetic mutation]], sporadic form (very rare)
| risks = Family history
| diagnosis = Suspected based on symptoms, supported by [[sleep study]], [[PET scan]] and [[genetic testing]] (if familial form is suspected)<ref name=GARD2019>{{cite web |title=Fatal familial insomnia |url=https://rarediseases.info.nih.gov/diseases/6429/fatal-familial-insomnia |website=Genetic and Rare Diseases Information Center (GARD) – an NCATS Program |access-date=17 May 2019}}</ref>
| differential = [[Alzheimer's disease]], [[frontotemporal dementia]], other [[Transmissible spongiform encephalopathy|transmissible spongiform encephalopathies]]<ref name=NORD2019>{{cite web |title=Fatal Familial Insomnia |url=https://rarediseases.org/rare-diseases/fatal-familial-insomnia/ |website=NORD (National Organization for Rare Disorders) |access-date=17 May 2019}}</ref>
| prevention = None
| treatment = [[Supportive care]]<ref name=Mer2019Pro/>
| medication = None
| prognosis = Invariably fatal
| frequency = 70 families worldwide are known to carry the gene associated with the disease, 37 sporadic cases diagnosed (as of 20 September 2022)
| deaths = <1 per year
}}
<!-- Definition and symptoms -->

'''Fatal insomnia''' is a [[neurodegenerative disease|neurodegenerative]] [[prion disease|disease]] that results in [[insomnia|trouble sleeping]] as its hallmark symptom.<ref name="Mer2019Pro" /> The majority of cases are familial ('''fatal familial insomnia''' ['''FFI''']), stemming from a mutation in the ''[[PRNP]]'' gene, with the remainder of cases occurring [[sporadic disease| sporadically]] ('''sporadic fatal insomnia''' ['''sFI''']). The problems with sleeping typically start out gradually and worsen over time.<ref name="NORD2019" /> Eventually, the patient will succumb to total insomnia (''agrypnia excitata''), most often leading to other symptoms such as [[Aphasia|speech problems]], coordination problems, and [[dementia]].<ref>{{cite book |url=https://www.merckmanuals.com/home/brain,-spinal-cord,-and-nerve-disorders/prion-diseases/fatal-insomnia |article=Fatal Insomnia |title=Merck Manual |access-date=4 May 2018}}</ref> It results in death within a few months to a few years, and there is no known [[disease-modifying treatment]].<ref name="Mer2019Pro" />

==Signs and symptoms==
The disease has four stages:<ref>{{cite web|url=http://www.world-of-lucid-dreaming.com/fatal-familial-insomnia.html|title=Dying To Sleep: Fatal Familial Insomnia (FFI) |vauthors=Turner R |website=www.world-of-lucid-dreaming.com |access-date=22 March 2018}}</ref>

# Characterized by worsening [[insomnia]], resulting in [[panic attack]]s, [[paranoia]], and [[phobia]]s. This stage lasts for about four months.
# [[Hallucination]]s and panic attacks become noticeable, continuing for about five months.
# Complete inability to [[sleep]] followed by rapid loss of [[weight]]. This lasts for about three months.
# [[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.
Clinically, Fatal Insomnia manifests with a disordered sleep-wake cycle, [[dysautonomia]], motor disturbances, and neuropsychiatric disorders.

Other symptoms include profuse sweating, [[miosis]] (pinpoint pupils), sudden entrance into [[menopause]] or [[impotence]], neck stiffness, and [[high blood pressure|elevation of blood pressure]] and heart rate. The sporadic form of the disease often presents with [[Diplopia|double vision]]. Prolonged 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 they were  dreaming.<ref name="Cortelli et al.">{{cite journal |vauthors=Cortelli P, Gambetti P, Montagna P, Lugaresi E |title=Fatal familial insomnia: clinical features and molecular genetics |journal=Journal of Sleep Research |volume=8 |issue=Suppl 1 |pages=23–29 |date=June 1999 |pmid=10389103 |doi=10.1046/j.1365-2869.1999.00005.x |s2cid=24399165}}</ref>

The age of onset is variable, ranging from 13 to 60 years, with an average of 50.<ref>{{cite web |title=Episode 25: Fatal Insomnia |url=https://www.obscuracrimepodcast.com/podcast/2018/10/10/episode-25-fatal-insomnia |website=Obscura: A True Crime Podcast}}</ref> The disease can be detected prior to onset by genetic testing.<ref>{{cite magazine |vauthors=Max DT |title=The Secrets of Sleep |url=https://www.nationalgeographic.com/magazine/article/sleep |magazine=National Geographic |volume=217 |issue=5 |date=May 2010 |page=74}}</ref> Death usually occurs between 6–36 months from onset. The presentation of the disease varies considerably from person to person, even among people within the same family; in the sporadic form, for example, sleep problems are not commonly reported, and early symptoms are [[ataxia]], cognitive impairment, and double vision.<ref>{{Cite web |url=https://www.merckmanuals.com/en-ca/professional/neurologic-disorders/prion-diseases/fatal-insomnia |title=Fatal Insomnia - Neurologic Disorders}}</ref>

==Cause==
{{Technical|section|date=September 2023}}
[[File:Location of PRNP-gene in chromosome 20.svg|thumb|250px|[[Idiogram]] of chromosome 20 showing gene'' PRP ''location]]
Fatal familial insomnia is a rare hereditary [[prion disease]] that is associated with a mutation in ''PRNP''. The gene, which provides instructions for making the [[prion protein]] PrP<sup>C</sup>, is located on the short arm of [[chromosome 20]] at position p13.<ref>{{cite web|url=https://medlineplus.gov/genetics/gene/prnp/ |title=PRNP gene |website=Genetics Home Reference |access-date=22 March 2018}}</ref> Individuals with FFI or familial [[Creutzfeldt–Jakob disease]] (fCJD) both 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 occurs when there is a change of [[amino acid]] at position 178 in which [[asparagine]] is found instead of the normal [[aspartic acid]]. This has to be accompanied with a methionine at position 129.<ref>{{cite book |vauthors=Khan Z, Sankari A, Bollu PC |title=StatPearls |date=2024 |publisher=StatPearls Publishing |chapter=Fatal Familial Insomnia |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK482208/ |pmid=29489284}}</ref>

FFI is an autosomal dominant disease caused by a [[Missense mutation|missense GAC-to-AAC mutation]] at codon 178 of the ''PRNP'' prion protein gene located on chromosome 20, along with the presence of the methionine polymorphism at position 129 of the mutant allele. Pathologically, FFI is characterized predominantly by [[Thalamus|thalamic]] degeneration{{em dash}}especially in the [[Medial dorsal nucleus|medio-dorsal]] and [[Anteroventral periventricular nucleus|anteroventral nuclei]].<ref>{{cite journal |vauthors=Xie K, Chen Y, Chu M, Cui Y, Chen Z, Zhang J, Liu L, Jing D, Cui C, Liang Z, Ren L, Rosa-Neto P, Ghorayeb I, Zhang Z, Wu L |title=Specific structuro-metabolic pattern of thalamic subnuclei in fatal familial insomnia: A PET/MRI imaging study |journal=NeuroImage. Clinical |volume=34 |article-number=103026 |date=2022 |pmid=35504222 |pmc=9065920 |doi=10.1016/j.nicl.2022.103026}}</ref> [[Phenotypic heterogeneity|Phenotypic variability]] is a perplexing feature of FFI.<ref>{{cite journal |vauthors=Zhang J, Chu M, Tian Z, Xie K, Cui Y, Liu L, Meng J, Yan H, Ji YM, Jiang Z, Xia TX, Wang D, Wang X, Zhao Y, Ye H, Li J, Wang L, Wu L |title=Clinical profile of fatal familial insomnia: phenotypic variation in 129 polymorphisms and geographical regions |journal=Journal of Neurology, Neurosurgery, and Psychiatry |volume=93 |issue=3 |pages=291–297 |date=March 2022 |pmid=34667102 |pmc=8862016 |doi=10.1136/jnnp-2021-327247}}</ref>

Prion diseases are caused by the accumulation of misfolded prion proteins in the brain. Generally, prion disorders are characterized by long incubation periods and short clinical duration, which means the abnormal prions may accumulate for many years without causing symptoms (long incubation period), but once symptoms begin the disorder rapidly worsens.

==Pathophysiology==
Given its striking clinical and neuropathologic similarities with fatal familial insomnia (FFI), a genetic prion disease linked to a point mutation at codon 178 (D178N) in the PRNP coupled with methionine at codon 129, the MM2T subtype is also known as sporadic FI (sFI). Transmission studies using susceptible transgenic mice have consistently demonstrated that the same prion strain is associated with both sFI and FFI. In contrast to what has been the rule for the most common neurodegenerative disorders, sFI is rarer than its genetic counterpart. Whereas the recognized patients with FFI are numerous and belong to >50 families worldwide, only about 30 cases of CJD MM2T and a few cases with mixed MM2T and MM2C features (MM2T+C) have been recorded to date.

In itself the presence of prions causes reduced glucose to be used by the [[thalamus]] and a mild hypo-metabolism of the [[cingulate cortex]]. The extent of this symptom varies between two variations of the disease: those presenting methionine [[homozygote]]s at codon 129 and methionine/valine [[heterozygote]]s, with some evidence that hypo-metabolism is more severe in the latter.<ref>{{cite journal |vauthors=Cortelli P, Perani D, Parchi P, Grassi F, Montagna P, De Martin M, Castellani R, Tinuper P, Gambetti P, Lugaresi E, Fazio F |title=Cerebral metabolism in fatal familial insomnia: relation to duration, neuropathology, and distribution of protease-resistant prion protein |journal=Neurology |volume=49 |issue=1 |pages=126–133 |date=July 1997 |pmid=9222180 |doi=10.1212/wnl.49.1.126}}</ref> 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 of insomnia.<ref>{{cite book |vauthors=Kostina A, Alama A, McGintya D, Alama N |chapter=Sleep homeostasis |title=Encyclopedia of Sleep and Circadian Rhythms |date=2023 |pages=39–47 |doi=10.1016/B978-0-12-822963-7.00243-7 |isbn=978-0-323-91094-1}}</ref><ref>{{cite journal |vauthors=Morton AJ |title=Circadian and sleep disorder in Huntington's disease |journal=Experimental Neurology |volume=243 |pages=34–44 |date=May 2013 |pmid=23099415 |doi=10.1016/j.expneurol.2012.10.014}}</ref>

==Diagnosis==
{{Technical|section|date=June 2024}}
Diagnosis is based on symptoms and can be supported by a [[sleep study]], a [[PET scan]] and [[genetic testing]] if the patient's family has a history of the disease. As with other prion diseases, the diagnosis can be confirmed only by a brain [[autopsy]]. 

The [[real-time quaking-induced conversion]] (RT-QuIC), a highly sensitive [[assay]] that detects minute amounts of PrP{{sup|Sc}} in the [[cerebrospinal fluid]], has been reported to have a sensitivity of 50% in FFI and sFI.<ref>{{cite journal |last1=Cracco |first1=L. |last2=Appleby |first2=B.S. |last3=Gambetti |first3=P. |title=Fatal familial insomnia and sporadic fatal insomnia |journal=Handbook of Clinical Neurology |date=2018 |volume=153 |pages=271–299 |doi=10.1016/B978-0-444-63945-5.00015-5 |pmid=29887141}}</ref><ref>{{cite journal |last1=Mok |first1=T.H. |last2=Nihat |first2=A. |last3=Luk |first3=C. |last4=Sequeira |first4=D. |last5=Batchelor |first5=M. |last6=Mead |first6=S. |last7=Collinge |first7=J. |last8=Jackson |first8=G.S. |title=Bank vole prion protein extends the use of RT-QuIC assays to detect prions in a range of inherited prion diseases |journal=Scientific Reports |date=4 March 2021 |volume=11 |issue=1 |page=5231 |doi=10.1038/s41598-021-84527-9 |doi-access=free|pmc=7933407}}</ref> However, this low sensitivity may change since the examination was based on a low number of cases, and the RT-QuIC technology is continuously evolving.{{contradictory inline|reason=Is the sensitivity low or high? The previous sentence says high, this one says low.|date=November 2025}}

A test that measures the [[cerebral metabolic rate]] of glucose by [[positron emission tomography]] (PET), referred to as [18F]-FDG-PET, has demonstrated severe [[hypometabolism]] of the thalamus bilaterally in FFI and sFI, also in the earliest stages of the disease. This hypometabolism then spreads, eventually impacting most cortical regions.<ref>{{cite journal |last1=Cortelli |first1=P. |last2=Perani |first2=D. |last3=Montagna |first3=P. |last4=Gallassi |first4=R. |last5=Tinuper |first5=P. |last6=Federica |first6=P. |last7=Avoni |first7=P. |last8=Ferrillo |first8=F. |last9=Anchisi |first9=D. |last10=Moresco |first10=R.M. |last11=Fazio |first11=F. |last12=Parchi |first12=P. |last13=Baruzzi |first13=A. |last14=Lugaresi |first14=E. |last15=Gambetti |first15=P. |title=Pre-symptomatic diagnosis in fatal familial insomnia: serial neurophysiological and 18FDG-PET studies |journal=Brain |date=1 March 2006 |volume=129 |issue=3 |pages=668–675 |doi=10.1093/brain/awl003 |pmid=16399807}}</ref> The complexity and cost of this test currently impedes its use in routine diagnosis.

===Differential diagnosis===
Other diseases involving the [[PRNP|mammalian prion protein]] are known.<ref name="PanegyresBurchell2016">{{cite journal |vauthors=Burchell JT, Panegyres PK |title=Prion diseases: immunotargets and therapy |journal=ImmunoTargets and Therapy |volume=5 |pages=57–68 |year=2016 |pmid=27529062 |pmc=4970640 |doi=10.2147/ITT.S64795 |doi-access=free}}</ref> Some are transmissible ([[transmissible spongiform encephalopathy|TSEs]], including FFI) such as [[kuru (disease)|kuru]], [[bovine spongiform encephalopathy]] (BSE, also known as mad cow disease) in cattle and [[chronic wasting disease]] in American [[deer]] and [[Elk|American elk]] in some areas of the United States and Canada, as well as [[Creutzfeldt–Jakob disease]] (CJD). Until recently, prion diseases were thought to be transmissible only 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.<ref>{{cite magazine |url=https://www.wired.com/wiredscience/2011/01/airborne-prions-disease/ |title=Airborne prions make for 100 percent lethal whiff |vauthors=Mosher D |magazine=[[Wired (magazine)|Wired]] |date=13 January 2011 |access-date=20 May 2011}}</ref>

==Treatments==
Treatment involves [[palliative care]].<ref name=Mer2019Pro /> There is conflicting evidence over the use of [[sleeping pill]]s, including [[barbiturate]]s, as a treatment for the disease.<ref>{{cite web |url=http://www.world-of-lucid-dreaming.com/the-man-who-never-slept.html |title=The man who never slept: Michael Corke |vauthors=Turner R |access-date=20 May 2011 |work=World of Lucid Dreaming}}</ref><ref name="Schenkein06" /> Symptoms of fatal familial insomnia may be treated with medications.{{Contradictory inline|date=July 2024}}

[[Clonazepam]] may be prescribed to treat muscle spasms, and [[eszopiclone]] or [[zolpidem]] may be prescribed to help treat insomnia. However, these drugs do not work in the long term.<ref>{{cite web |title=Fatal familial insomnia: Everything you need to know |url=https://www.medicalnewstoday.com/articles/fatal-familial-insomnia |website=MedicalNewsToday |access-date=27 February 2023 |language=en |date=14 April 2020}}</ref>{{Better source needed|date=July 2024}}

==Prognosis==
[[File:FFI timeline.svg|thumb|Timeline of a fatal familial insomnia (FFI) patient]]
Like all prion diseases, FFI is invariably fatal.<ref name="Schenkein06">{{cite journal |vauthors=Schenkein J, Montagna P |title=Self management of fatal familial insomnia. Part 1: what is FFI? |journal=MedGenMed |volume=8 |issue=3 |pages=65 |date=September 2006 |pmid=17406188 |pmc=1781306}}</ref><ref name="Mer2019Pro" /> Life expectancy ranges from seven months to six years,<ref name="Mer2019Pro" /> with an average of 18 months.<ref name="Schenkein06" />

==Epidemiology and history==
[[File:FFI Diagrams.svg|thumb|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.)]]
Fatal insomnia was first described by Elio Lugaresi et al. in 1986.

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.<ref>{{cite journal |vauthors=Montagna P, Gambetti P, Cortelli P, Lugaresi E |title=Familial and sporadic fatal insomnia |journal=The Lancet. Neurology |volume=2 |issue=3 |pages=167–176 |date=March 2003 |pmid=12849238 |doi=10.1016/S1474-4422(03)00323-5 |s2cid=20822956}}</ref> In the [[Basque Country (autonomous community)|Basque Country]] of 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.<ref>{{cite journal |vauthors=Parchi P, Capellari S, Chin S, Schwarz HB, Schecter NP, Butts JD, Hudkins P, Burns DK, Powers JM, Gambetti P |title=A subtype of sporadic prion disease mimicking fatal familial insomnia |journal=Neurology |volume=52 |issue=9 |pages=1757–1763 |date=June 1999 |pmid=10371520 |doi=10.1016/S0304-4858(07)74572-9 |doi-access=free}}</ref> In 2011, another family was added to the list when researchers found the first man in the Netherlands to be diagnosed with FFI. Whilst he had lived in the Netherlands for 19 years, he was of Egyptian descent.<ref name="Jansen et al." /> Other prion diseases are similar to FFI and may be related but are missing the ''D178N'' gene mutation.<ref name="Cortelli et al." />

{{as of|2022|9|20}}, 37 cases of sporadic fatal insomnia have been diagnosed.<ref name=GARD2019 /> Unlike in FFI, those with sFI do not have the ''D178N'' mutation in the ''PRNP'' gene; they all have a different mutation in the same gene causing [[methionine]] [[homozygosity]] at [[codon]] 129.<ref>{{cite journal |vauthors=Mehta LR, Huddleston BJ, Skalabrin EJ, Burns JB, Zou WQ, Gambetti P, Chin SS |title=Sporadic fatal insomnia masquerading as a paraneoplastic cerebellar syndrome |journal=Archives of Neurology |volume=65 |issue=7 |pages=971–973 |date=July 2008 |pmid=18625868 |doi=10.1001/archneur.65.7.971 |doi-access=free}}</ref><ref>{{cite journal |vauthors=Moody KM, Schonberger LB, Maddox RA, Zou WQ, Cracco L, Cali I |title=Sporadic fatal insomnia in a young woman: a diagnostic challenge: case report |journal=BMC Neurology |volume=11 |article-number=136 |date=October 2011 |pmid=22040318 |pmc=3214133 |doi=10.1186/1471-2377-11-136 |doi-access=free |department=Case report}}</ref> Nonetheless, the methionine presence in lieu of the valine (Val129) is what causes the sporadic form of disease. The targeting of this mutation has been suggested as a strategy for treatment, or possibly as a cure for the disease.<ref>{{cite journal |vauthors=Tabaee Damavandi P, Dove MT, Pickersgill RW |title=A review of drug therapy for sporadic fatal insomnia |journal=Prion |volume=11 |issue=5 |pages=293–299 |date=September 2017 |pmid=28976233 |pmc=5639864 |doi=10.1080/19336896.2017.1368937 |doi-access=free}}</ref>

===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.<ref name="pmid17406189">{{cite journal |vauthors=Schenkein J, Montagna P |title=Self-management of fatal familial insomnia. Part 2: case report |journal=MedGenMed |volume=8 |issue=3 |pages=66 |date=September 2006 |pmid=17406189 |pmc=1781276}}</ref>

In 1986, Lugaresi and colleagues first named and described in detail the clinical and histopathological features of fatal familial insomnia.<ref>{{cite journal |last1=Lugaresi |first1=E. |last2=Medori |first2=R. |last3=Montagna |first3=P. |last4=Baruzzi |first4=A. |last5=Cortelli |first5=P. |last6=Lugaresi |first6=A. |last7=Tinuper |first7=P. |last8=Zucconi |first8=M. |last9=Gambetti |first9=P. |date=1986-10-16 |title=Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei |journal=The New England Journal of Medicine |volume=315 |issue=16 |pages=997–1003 |doi=10.1056/NEJM198610163151605 |issn=0028-4793 |pmid=3762620 }}</ref> This report was primarily based on the aforementioned Silvano. Dr. Roiter referred the case to Prof. Elio Lugaresi, a well-known sleep expert, who, along with his colleagues, carried out advanced sleep analyses. As Silvano's condition quickly deteriorated, Lugaresi arranged for a postmortem neuropathological examination of the brain to be carried out by Dr. Gambetti, Lugaresi's former trainee. The collaboration of these two groups led to the 1986 publication.<ref name="Jansen et al." /> At the time, a prion disease was not suspected due to a lack of prion-related histopathology and frozen brain tissue for advanced analysis. However, due to the devotion of Dr. Roiter and Silvano's family, more cases were obtained, resulting in the classification of FFI as a familial prion disease tied to the 178Asn genetic mutation.<ref>{{cite journal |last1=Medori |first1=R. |last2=Tritschler |first2=H. J. |last3=LeBlanc |first3=A. |last4=Villare |first4=F. |last5=Manetto |first5=V. |last6=Chen |first6=H. Y. |last7=Xue |first7=R. |last8=Leal |first8=S. |last9=Montagna |first9=P. |last10=Cortelli |first10=P. |date=1992-02-13 |title=Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene |journal=The New England Journal of Medicine |volume=326 |issue=7 |pages=444–449 |doi=10.1056/NEJM199202133260704 |issn=0028-4793 |pmc=6151859 |pmid=1346338 |doi-access=free}}</ref>

===Unnamed American patient, 2001===
In an article published in 2006, Schenkein and Montagna wrote of a 52-year-old American man who was able to exceed the average survival time by nearly one year with various strategies that included vitamin therapy and [[meditation]], 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 man succumbed to the classic four-stage progression of the illness.<ref name="pmid17406189" />

===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. Whilst he tended to fall asleep at random during 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.<ref name="Jansen et al.">{{cite journal |vauthors=Jansen C, Parchi P, Jelles B, Gouw AA, Beunders G, van Spaendonk RM, van de Kamp JM, Lemstra AW, Capellari S, Rozemuller AJ |title=The first case of fatal familial insomnia (FFI) in the Netherlands: a patient from Egyptian descent with concurrent four repeat tau deposits |journal=Neuropathology and Applied Neurobiology |volume=37 |issue=5 |pages=549–553 |date=August 2011 |pmid=20874730 |doi=10.1111/j.1365-2990.2010.01126.x |s2cid=30722366}}</ref>

==Research==
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]].<ref name="GARD2019" /> {{As of|2016}}, a study investigating [[doxycycline]] is being carried out.<ref name="GARD2019" /><ref>{{cite journal |vauthors=Forloni G, Tettamanti M, Lucca U, Albanese Y, Quaglio E, Chiesa R, Erbetta A, Villani F, Redaelli V, Tagliavini F, Artuso V, Roiter I |title=Preventive study in subjects at risk of fatal familial insomnia: Innovative approach to rare diseases |journal=Prion |volume=9 |issue=2 |pages=75–79 |date=21 May 2015 |pmid=25996399 |pmc=4601344 |doi=10.1080/19336896.2015.1027857}}</ref>

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.<ref>{{cite journal |vauthors=Jackson WS, Borkowski AW, Faas H, Steele AD, King OD, Watson N, Jasanoff A, Lindquist S |title=Spontaneous generation of prion infectivity in fatal familial insomnia knockin mice |journal=Neuron |volume=63 |issue=4 |pages=438–450 |date=August 2009 |pmid=19709627 |pmc=2775465 |doi=10.1016/j.neuron.2009.07.026}}</ref> 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.{{citation needed|date=June 2022}}

The Prion Alliance was established by husband and wife duo Eric Minikel and [[Sonia M. Vallabh|Sonia Vallabh]] after Vallabh's mother was diagnosed with the fatal disease.<ref>{{cite magazine |vauthors=Clancy K |title=One Couple's Tireless Crusade to Stop a Genetic Killer |url=https://www.wired.com/story/sleep-no-more-crusade-genetic-killer/ |magazine=Wired |date=15 January 2019}}</ref> They conduct research at the [[Broad Institute]] to develop therapeutics for human prion diseases. Their hypothesis is that lowering PrP-levels may prevent the onset of FFI.<ref>{{Cite web |title=Driving at Night in the Fog: Sonia Vallabh and Eric Minikel's Unique Path to a Cure for Prion Disease |url=https://www.massgeneral.org/neurology/news/vallabh-minikel-path-to-cure-for-prion-disease |archive-url=https://web.archive.org/web/20250322144435/https://www.massgeneral.org/neurology/news/vallabh-minikel-path-to-cure-for-prion-disease |archive-date=22 March 2025 |access-date=2025-05-24 |website=Massachusetts General Hospital |language=en |url-status=live}}</ref> Other research interests involve identifying [[biomarker]]s to track the progression of prion disease in living people.<ref>{{Cite web|url=https://www.broadinstitute.org/bios/sonia-vallabh|title=Sonia Vallabh|date=2015-08-20|website=Broad Institute|language=en|access-date=2019-01-21}}{{self-published inline|date=June 2024}}</ref><ref>{{Cite web|url=http://www.prionalliance.org/|title=Prion Alliance|website=www.prionalliance.org|access-date=2019-01-21}}{{self-published inline|date=June 2024}}</ref>

==References==
{{Reflist}}

==External links==
* {{cite web |url=http://www.afiff.net/ |title=AFIFF Fatal Familial Insomnia Families Association |access-date=26 January 2013 |archive-date=21 October 2016 |archive-url=https://web.archive.org/web/20161021083654/http://www.afiff.net/ |url-status=dead}}

{{Medical resources
| DiseasesDB      = 32177
| ICD11           = {{ICD11|8E02.2}}
| ICD10CM         = {{ICD10CM|A81.83}}
| ICD9            = {{ICD9|046.72}}
| ICDO            =
| OMIM            = 600072
| MedlinePlus     =
| eMedicineSubj   =
| eMedicineTopic  =
| MeshID          = D034062
}}

{{Prion diseases}}
{{Authority control}}

{{DEFAULTSORT:Fatal Familial Insomnia}}
[[Category:Neurodegenerative disorders]]
[[Category:Transmissible spongiform encephalopathies]]
[[Category:Unsolved problems in neuroscience]]
[[Category:Sleep disorders]]
[[Category:Rare diseases]]
[[Category:Sleeplessness and sleep deprivation]]