|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|
|Causes||Genetic mutation, sporadic form very rare|
|Risk factors||Family history|
|Diagnostic method||Brain biopsy|
|Differential diagnosis||Creutzfeldt-Jakob disease|
|Treatment||Supportive, but all cases end in death|
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.
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.
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. The average survival time for patients diagnosed with FFI after the onset of symptoms is 18 months.
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.
- 1 Presentation
- 2 Cause
- 3 Cases
- 4 Treatments and research
- 5 Epidemiology
- 6 Related conditions
- 7 In popular culture
- 8 References
- 9 External links
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. 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:
- The person has increasing insomnia, resulting in panic attacks, paranoia, and phobias. This stage lasts for about 4 months.
- Hallucinations and panic attacks become noticeable, continuing for about 5 months.
- Complete inability to sleep is followed by rapid loss of weight. This lasts for about 3 months.
- 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.
Gene PRNP that provides instructions for making the prion protein PrPC is located on the short (p) arm of chromosome 20 at position p13. 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."
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.
Michael Corke, 1991, United States
One of the most notable cases is that of Michael Corke, a music teacher from New Lenox, 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 where physicians were initially puzzled by his presentation. As his course progressed, physicians attempted to induce a coma with the use of sedatives. Nevertheless 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.
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.
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.
Treatments and research
Sleeping pills[clarification needed] 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.[disputed ]
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. 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.
It was reported in 1998 that 100 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. 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. 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. Other prion diseases are similar to FFI and could be related, but are missing the D178N gene mutation.
Only 9 cases of sporadic fatal insomnia have ever been diagnosed as of July 2005[update]. 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.
Other diseases involving the mammalian prion protein are known. 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.
In popular culture
In Something's Killing Me with BD Wong, November 2017 (season one, episode five), "Family Curse", FFI is the topic.
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|url=(help). Discovery Channel.
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