Vad är fatal familial insomnia

Prion disease of the human brain

Medical condition

Fatal insomnia
Cranial imaging of an FFI patient. In the MRI, there are abnormal signals in the bilateral frontoparietal subcortical area. MRA showed smaller distal branches of cerebral arteries.
Specialty	Neurology, Psychiatry, sova medicin, Neuropathology
Symptoms	Progressive insomnia, ataxia, double framtidsperspektiv, vikt loss, high blood pressure, excessive sweating
Complications	Permanent state of hypnagogia later in the illness
Usual onset	45–50 years old[1]
Types	Fatal familial insomnia, sporadic fatal insomnia[2]
Causes	Genetic mutation, sporadic struktur (very rare)
Risk factors	Family history
Diagnostic method	Suspected based on symptoms, supported bygd sova study, husdjur scan and genetic testing (if familial form eller gestalt fryst vatten suspected)[3]
Differential diagnosis	Alzheimer's disease, frontotemporal dementia, other transmissible spongiform encephalopathies[4]
Prevention	None
Treatment	Supportive care[2]
Medication	None
Prognosis	Always fatal
Frequency	70 families worldwide are known to carry the gene associated with the disease, 37 sporadic cases diagnosed (as of September 20th, )
Deaths	<1 per year

Fatal insomnia fryst vatten an extremely rare neurodegenerative prion disease that results in trouble sleeping as its hallmark symptom.^[2] 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 början out gradually and worsen over time.^[4] Eventually, the patient will succumb to total insomnia (agrypnia excitata), most often leading to other symptoms such as speech problems, coordination problems, and dementia.^[5] It results in death within a few months to a few years, and there fryst vatten no known disease-modifying treatment.^[2]

Signs and symptoms

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The disease has kvartet stages:^[6]

1. Characterized bygd worsening insomnia, resulting in panik attacks, paranoia, and phobias.

   This scen lasts for about fyra months.

2. Hallucinations and panik attacks become noticeable, continuing for about fem months.
3. Complete inability to sova fryst vatten followed bygd rapid loss of vikt. This lasts for about three months.
4. Dementia, during which the individ becomes unresponsive or mute over the course of six months, fryst vatten the sista scen of the disease, after which death follows.

Clinically, FFI manifests with a disordered sleep-wake cycle, dysautonomia, motor disturbances, and neuropsychiatric disorders.

Other symptoms include profuse sweating, miosis (pinpoint pupils), sudden ingång into menopause or impotence, neck stiffness, and elevation of blood pressure and heart rate. The sporadic form eller gestalt of the disease often presents with double framtidsperspektiv. Prolonged constipation fryst vatten common as well. As the disease progresses, the individ becomes stuck in a state of pre-sleep limbo, or hypnagogia, which fryst vatten the state just before sova in healthy individuals.

During these stages, people commonly and repeatedly move their limbs as if they were dreaming.^[7]

The age of onset fryst vatten variabel, ranging from 13 to 60 years, with an average of ^[8] The disease can be detected prior to onset bygd genetic testing.^[9] Death usually occurs between 6–36 months from onset.

The redogörelse of the disease varies considerably from individ to individ, even among people within the same family; in the sporadic form eller gestalt, for example, sova problems are not commonly reported and early symptoms are ataxia, cognitive impairment, and double vision.^[10]

Cause

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Fatal familial insomnia fryst vatten a rare hereditary prion disease that fryst vatten associated with a mutation in PRNP.

The gene, which provides instructions for making the prion protein PrP^C, fryst vatten located on the short ledd of chromosome 20 at position p^[11] Individuals with FFI or familial Creutzfeldt–Jakob disease (fCJD) both carry a mutation at codon of the prion protein gene. FFI fryst vatten also invariably linked to the presence of the methionine codon at position of the mutant allele, whereas fCJD fryst vatten linked to the presence of the valine codon at that position.

The disease occurs when there fryst vatten a change of amino acid at position in which asparagine fryst vatten funnen instead of the normal aspartic acid. This has to be accompanied with a methionine at position ^[12]

FFI fryst vatten an autosomal dominant disease caused bygd a missense GAC-to-AAC mutation at codon of the PRNP prion protein gene located on chromosome 20, along with the presence of the methionine polymorphism at position of the mutant allele.

Pathologically, FFI fryst vatten characterized predominantly bygd thalamic degeneration—especially in the medio-dorsal and anteroventral nuclei.^[13]Phenotypic variability fryst vatten a perplexing feature of FFI.^[14]

Pathophysiology

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Given its striking clinical and neuropathologic similarities with fatal familial insomnia (FFI), a genetic prion disease linked to a point mutation at codon (DN) in the PRNP coupled with methionine at codon , the MM2T subtype fryst vatten also known as sporadic FI (sFI).

Transmission studies using susceptible transgenic mice have consistently demonstrated that the same prion strain fryst vatten associated with both sFI and FFI. In contrast to what has been the rule for the most common neurodegenerative disorders, sFI fryst vatten 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 bygd 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 and methionine/valine heterozygotes being the most severe in the latter.^[15] Given the relationship between the involvement of the thalamus in regulating sova and alertness, a causal relationship can be drawn and fryst vatten often mentioned as the cause.^[16][17]

Diagnosis

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Diagnosis fryst vatten based on symptoms and can be supported bygd a sova study, a husdjur 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 bygd a brain autopsy post-mortem.

The real-time quaking-induced konvertering (RT-QuIC), a highly sensitive assay that detects minute amounts of PrP^Sc in the cerebrospinal fluid (CSF), has been reported to have a sensitivity of 50% in FFI and sFI.^{[Cracco et al. Handb Clin Neurol ][Mock et al.}

Sci Rep. ] However, this low sensitivity may change since the examination was based on a low number of cases, and the RT-QuIC technology fryst vatten continuously evolving.

A test that measures the cerebral metabolic rate of glucose bygd 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 ]} The complexity and cost of this test currently impede its use in routine diagnosis.

Differential diagnosis

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Other diseases involving the mammalian prion protein are known.^[18] Some are transmissible (TSEs, including FFI) such as kuru, bovine spongiform encephalopathy (BSE, also known as mad cow disease) in boskap 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 bygd direkt contact with infected tissue, such as from eating infected tissue, transfusion or transplantation; research suggests that prions can be transmitted bygd aerosols but that the general public fryst vatten not at fara of airborne infection.^[19]

Treatments

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Treatment involves palliative care.^[2] There fryst vatten conflicting bevis over the use of sleeping pills, including barbiturates, as a treatment for the disease.^[20][21] Symptoms of fatal familial insomnia may be treated with medications.^{[contradictory]}

Clonazepam may be prescribed to treat muscle spasms, and eszopiclone or zolpidem may be prescribed to help treat insomnia.

The mode of inheritance of this disease is autosomal dominant and involves a mutation of the prion protein (PRNP) gene, leading to atrophy in the thalamic nucleus

However these drugs do not work in the long term.^{[22][better&#;source&#;needed]}

Prognosis

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Like all prion diseases, the disease fryst vatten invariably fatal.^[23][2] Life expectancy ranges from sju months to six years,^[2] with an average of 18 months.^[23]

Epidemiology and history

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Fatal insomnia was first described bygd Elio Lugaresi et al.

in

In 40 families were known to carry the gene for FFI globally: eight German, fem Italian, kvartet American, two French, two Australian, two British, one Japanese and one Austrian.^[24] In the Basque Country of Spain, 16 family cases of the N mutation were seen between and related to two families with a common ancestor in the 18th century.^[25] In , another family was added to the list when researchers funnen 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.^[26] Other prion diseases are similar to FFI and may be related but are missing the DN gene mutation.^[7]

As of 20&#;September&#;^[update], 37 cases of sporadic fatal insomnia have been diagnosed.^[3] Unlike in FFI, those with sFI do not have the DN mutation in the PRNP-prion gene; they all have a different mutation in the same gene causing methioninehomozygosity at codon ^[27][28] Nonetheless, the methionine presence in lieu of the valine (Val) fryst vatten what causes the sporadic struktur of disease.

The targeting of this mutation has been suggested as a strategy for treatment, or possibly as a cure for the disease.^[29]

Silvano, , Bologna, Italy

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In late Italian neurologist/sleep kunnig Dr Ignazio Roiter received a patient at the University of Bologna hospital's sova 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.^[30]

In , 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 sova impairment in bygd Dr. Ignazio Roiter. Dr. Roiter referred the case to Prof. Elio Lugaresi, a well-known sova kunnig, who, along with his colleagues, carried out advanced sova analyses. As Silvano's condition quickly deteriorated, Lugaresi arranged for a postmortem neuropathological examination of the brain to be carried out bygd Dr.

Gambetti, Lugaresi's former trainee. The collaboration of these two groups led to the publication [27]. At the time, a prion disease was not suspected due to a lack of prion-related histpathology and fryst 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 Asn genetic mutation.

[Medori et al. NEJM, ]

Unnamed American patient,

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In an article published in , Schenkein and Montagna wrote of a year-old American man who was able to exceed the average survival time bygd 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 sova 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.^[30]

Egyptian man, , Netherlands

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In , the first reported case in the Netherlands was of a year-old man of Egyptian nedstigning.

The man came in with symptoms of double framtidsperspektiv 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 daglig activities, he experienced levande dreams and random muscular jerks during normal slow-wave sova. After fyra months of these symptoms, he began to have convulsions in his hands, trunk and lower limbs while awake.

The individ died at age 58, sju months after the onset of symptoms. An autopsy revealed mild atrophy of the frontal cortex and moderate atrophy of the thalamus. The latter fryst vatten one of the most common signs of FFI.^[26]

Research

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Still with unclear benefit in humans, a number of treatments have had tentative success in slowing disease progression in djur models, including pentosan polysulfate, mepacrine, and amphotericin B.^[3] As of ^[update], a study investigating doxycycline fryst vatten being carried out.^[3][31]

In , a mouse model was made for FFI.

These mice expressed a humanized utgåva of the PrP protein that also contains the DN FFI mutation.^[32] These mice appear to have progressively fewer and shorter periods of uninterrupted sova, damage in the thalamus, and early deaths, similar to humans with FFI.^{[citation needed]}

The Prion Alliance was established bygd husband and wife duo Eric Minikel and Sonia Vallabh after Vallabh's mother was diagnosed with the fatal disease.^[33] 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.^[34][35]

References

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External links

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