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Fatal insomnia is a neurodegenerative prion disease that results in insomnia as its hallmark symptom. 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 ( sporadic fatal insomnia sFI). The problems with sleeping typically start out gradually and worsen over time. Eventually, the patient will succumb to total insomnia ( agrypnia excitata), most often leading to other symptoms such as Aphasia, coordination problems, and dementia. It results in death within a few months to a few years, and there is no known disease-modifying treatment.
Other symptoms include profuse sweating, miosis (pinpoint pupils), sudden entrance into menopause or impotence, neck stiffness, and elevation of blood pressure and heart rate. The sporadic form of the disease often presents with Diplopia. 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.
The age of onset is variable, ranging from 13 to 60 years, with an average of 50. The disease can be detected prior to onset by genetic testing. 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.
FFI is an autosomal dominant disease caused by a 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 degenerationespecially in the medio-dorsal and anteroventral nuclei. Phenotypic variability is a perplexing feature of FFI.
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.
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 at codon 129 and methionine/valine , with some evidence that hypo-metabolism is more severe in the latter. 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. (2025). 9780323910941 ISBN 9780323910941
The real-time quaking-induced conversion (RT-QuIC), a highly sensitive assay that detects minute amounts of PrPSc in the cerebrospinal fluid, has been reported to have a sensitivity of 50% in FFI and sFI.Cracco et al. Handbook of Clinical Neurology 2018Mock et al. Scientific Reports 2021 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.
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.Cortelli et al. Brain 2006 The complexity and cost of this test currently impedes its use in routine diagnosis.
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.
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. In the 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. 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. Other prion diseases are similar to FFI and may be related but are missing the D178N gene mutation.
, 37 cases of sporadic fatal insomnia have been diagnosed. 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.
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.
In 1986, Lugaresi and colleagues first named and described in detail the clinical and histopathological features of fatal familial insomnia. 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. 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.
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.
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. 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. Other research interests involve identifying to track the progression of prion disease in living people.
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.
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.
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.
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. , a study investigating doxycycline is being carried out.
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