Fatal insomnia

Fatal insomnia is an extremely rare neurodegenerative prion disease that results in trouble sleeping 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 sporadically (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 speech problems, coordination problems, and dementia. It results in death within a few months to a few years, and there is no known disease-modifying treatment.

Signs and symptoms
The disease has four stages:

Clinically, FFI manifests with a disordered sleep-wake cycle, dysautonomia, motor disturbances, and neuropsychiatric disorders.
 * 1) Characterized by worsening 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, 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 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.

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.

Cause
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 PrPC, is located on the short arm of chromosome 20 at position p13. 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.

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 thalamic degeneration—especially in the medio-dorsal and anteroventral nuclei. Phenotypic variability is a perplexing feature of FFI.

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, these being those presenting methionine homozygotes at codon 129 and methionine/valine heterozygotes being the most 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.

Diagnosis
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 post-mortem.

The real-time quaking-induced conversion (RT-QuIC), a highly sensitive assay that detects minute amounts of PrPSc in the cerebrospinal fluid (CSF), has been reported to have a sensitivity of 50% in FFI and sFI.[Cracco et al. Handb Clin Neurol 2018][Mock et al. Sci Rep. 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 impede its use in routine diagnosis.

Differential diagnosis
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 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.

Treatments
Treatment involves palliative care. There is conflicting evidence over the use of sleeping pills, including barbiturates, as a treatment for the disease. Symptoms of fatal familial insomnia may be treated with medications.

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.

Prognosis
Like all prion diseases, the disease is invariably fatal. Life expectancy ranges from seven months to six years, with an average of 18 months.

Epidemiology and history
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. 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-prion 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.

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.

In 1986, Lugaresi and colleagues first named and described in detail the clinical and histopathological features of fatal familial insomnia (FFI) [Lugaresi et al. NEJM]. This report was mostly based on a patient referred to as Silvano, who was diagnosed with sleep impairment in 1983 by Dr. Ignazio Roiter. 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 [27]. At the time, a prion disease was not suspected due to a lack of prion-related histpathology 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. [Medori et al. NEJM, 1992]

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.

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. Other research interests involve identifying biomarkers to track the progression of prion disease in living people.