Fatal insomnia

The disease has four stages:[8]

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. The sporadic form of the disease often presents with double vision. 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.[9]

The age of onset is variable, ranging from 18 to 60 years, with an average of 50.[10] The disease can be detected prior to onset by genetic testing.[11] 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.

Idiogram of chromosome 20 showing gene PRP location

The gene PRNP that provides instructions for making the prion protein PrP^C is located on the short (p) arm of chromosome 20 at position p13.[12] 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."[13]

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.[14] 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 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]

Treatment involves palliative care.[2] Sleeping pills, including barbiturates, have not been found to be helpful; contrarily, they have been suggested to worsen the symptoms.[17]

Similar to other prion diseases, the disease is invariably fatal.[6][2] Life expectancy ranges from seven months to six years,[2] with an average of 18 months.[6]

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.[18] 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.[19] 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.[20] Other prion diseases are similar to FFI and could be related, but are missing the D178N gene mutation.[9]

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.[21][22] Nonetheless the methionine presence in lieu of the valine (Val129) is what causes the sporadic form of disease. The targeting of this mutation is another strategy that has been suggested as possible for treatment, or hopefully as cure for the disease.[23]

Egyptian man, 2011, Netherlands

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.[20]

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, 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's mother 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]

• In the 2018 novel and online short story series "Tales from the Gas Station" the main character, Jack, believes that he suffers from fatal familial insomnia.
• Charlie Huston's 2010 novel Sleepless concerns an epidemic of a fatal insomnia that is frequently compared to FFI by characters in the story.
• In Something's Killing Me with BD Wong, November 2017 (season one, episode five), "Family Curse", FFI is the topic.[31]
• Nancy Kress's novelette Pathways concerns research into FFI.[32]
• 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.
• 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." It also features this Wikipedia article about the disease depicted in a book encyclopedia (Episode 6, 9:44).
• In the novel Siphonophore by Jaimie Batchan (2021), the fictional author of the book is diagnosed with a disease referred to as Prionic Fatal Insomnia midway through writing the novel.[33]
• Fatal familial insomnia induced by genetic engineering is part of the backstory of Destiny 2: Beyond Light.[34]
• Law and Order: Special Victims Unit, season 12, episode 19 - Dr. Huang diagnoses a witness who suffers from fatal familial insomnia. The witness is disoriented; unable to sleep; sweats severely and presents altered pupils. Dr. Huang explains to Detectives Olivia and Elliot that the referred disease mainly affects people from a small town in Italy, where the witness came from.

• "AFIFF Fatal Familial Insomnia Families Association".