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 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 person 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 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 supportive care.[2] Sleeping pills, including barbiturates, have not been found to be helpful; on the contrary, in 74% of cases, they have been shown to worsen the symptoms and hasten the course of the disease.[17]

The disease is invariably fatal.[6][2] Life expectancy ranges from 7 months to 6 years;[2] with an average of 18 months.[6]

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

In 1998 40 families are known to carry the gene for FFI globally: 8 German, 5 Italian, 4 American, 2 French, 2 Australian, 2 British, 1 Japanese, and 1 Austrian.[18] In the Basque Country, Spain, 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.[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]

Egyptian man, 2011, Netherlands

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

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 person 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.[20]

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

Nancy Kress' novelette Pathways concerns research into FFI.[27]

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][28]

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.[29] 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.[30] 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.[31][32]

• "AFIFF Fatal Familial Insomnia Families Association".