Fatal Familial Insomnia
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Fatal insomnia is an extremely rare
neurodegenerative A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, mul ...
prion disease that results in trouble sleeping as its hallmark symptom. The majority of cases are familial (fatal familial insomnia FI, stemming from a mutation in the ''
PRNP The major prion protein (PrP) is encoded in the human body by the ''PRNP'' gene also known as CD230 (cluster of differentiation 230). Expression of the protein is most predominant in the nervous system but occurs in many other tissues throughou ...
'' gene, with the remainder of cases occurring sporadically (sporadic fatal insomnia FI. 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 Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
. It results in death within a few months to a few years, and there is no known
disease-modifying treatment A disease-modifying treatment, disease-modifying drug, or disease-modifying therapy is a treatment that delays, slows or reverses the progression of a disease by targeting its underlying cause. They are distinguished from symptomatic treatments th ...
.


Signs and symptoms

The disease has four stages: # Characterized by worsening
insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
, resulting in
panic attack Panic attacks are sudden periods of intense fear and Comfort, discomfort that may include palpitations, otherwise defined as a Tachycardia, rapid, Arrhythmia, irregular Heart rate, heartbeat, Hyperhidrosis, sweating, chest pain or discomfort, s ...
s,
paranoia Paranoia is an instinct or thought process that is believed to be heavily influenced by anxiety, suspicion, or fear, often to the point of delusion and irrationality. Paranoid thinking typically includes persecutory beliefs, or beliefs of co ...
, and
phobia A phobia is an anxiety disorder, defined by an irrational, unrealistic, persistent and excessive fear of an object or situation. Phobias typically result in a rapid onset of fear and are usually present for more than six months. Those affected ...
s. This stage lasts for about four months. #
Hallucination A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...
s and panic attacks become noticeable, continuing for about five months. # Complete inability to
sleep Sleep is a state of reduced mental and physical activity in which consciousness is altered and certain Sensory nervous system, sensory activity is inhibited. During sleep, there is a marked decrease in muscle activity and interactions with th ...
is followed by rapid loss of
weight In science and engineering, the weight of an object is a quantity associated with the gravitational force exerted on the object by other objects in its environment, although there is some variation and debate as to the exact definition. Some sta ...
. This lasts for about three months. #
Dementia Dementia is a syndrome associated with many neurodegenerative diseases, characterized by a general decline in cognitive abilities that affects a person's ability to perform activities of daily living, everyday activities. This typically invo ...
, 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. Clinically, FFI manifests with a disordered sleep-wake cycle,
dysautonomia Dysautonomia, autonomic failure, or autonomic dysfunction is a condition in which the autonomic nervous system (ANS) does not work properly. This condition may affect the functioning of the heart, bladder, intestines, sweat glands, pupils, and ...
, motor disturbances, and neuropsychiatric disorders. Other symptoms include profuse sweating,
miosis Miosis, or myosis (), is excessive constriction of the pupil.Farlex medical dictionary
citing: ...
(pinpoint pupils), sudden entrance into
menopause Menopause, also known as the climacteric, is the time when Menstruation, menstrual periods permanently stop, marking the end of the Human reproduction, reproductive stage for the female human. It typically occurs between the ages of 45 and 5 ...
or
impotence Erectile dysfunction (ED), also referred to as impotence, is a form of sexual dysfunction in males characterized by the persistent or recurring inability to achieve or maintain a Human penis, penile erection with sufficient rigidity and durat ...
, neck stiffness, and elevation of blood pressure and heart rate. The sporadic form of the disease often presents with
double vision Diplopia is the simultaneous perception of two images of a single object that may be displaced in relation to each other. Also called double vision, it is a loss of visual focus under regular conditions, and is often voluntary. However, when occ ...
. Prolonged constipation is common as well. As the disease progresses, the person becomes stuck in a state of pre-sleep limbo, or
hypnagogia Hypnagogia is the transitional state from wakefulness to sleep, also defined as the waning state of consciousness during the onset of sleep. Its corresponding state is '' hypnopompia'' sleep to wakefulness. Mental phenomena that may occur duri ...
, 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 Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...
, cognitive impairment, and double vision.


Cause

Fatal familial insomnia is a rare hereditary
prion A prion () is a Proteinopathy, misfolded protein that induces misfolding in normal variants of the same protein, leading to cellular death. Prions are responsible for prion diseases, known as transmissible spongiform encephalopathy (TSEs), w ...
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 Chromosome 20 is one of the 23 pairs of chromosomes in humans. Chromosome 20 spans around 66 million base pairs (the building material of DNA) and represents between 2 and 2.5 percent of the total DNA in cells. Chromosome 20 was fully sequenced i ...
at position p13. Individuals with FFI or familial
Creutzfeldt–Jakob disease Creutzfeldt–Jakob disease (CJD) is an incurable, always fatal neurodegenerative disease belonging to the transmissible spongiform encephalopathy (TSE) group. Early symptoms include memory problems, behavioral changes, poor coordination, visu ...
(fCJD) both carry a mutation at
codon Genetic code is a set of rules used by living cells to translate information encoded within genetic material (DNA or RNA sequences of nucleotide triplets or codons) into proteins. Translation is accomplished by the ribosome, which links prote ...
178 of the prion protein gene. FFI is also invariably linked to the presence of the
methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other non-essential amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine play ...
codon at position 129 of the mutant allele, whereas fCJD is linked to the presence of the
valine Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deproton ...
codon at that position. The disease occurs when there is a change of
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
at position 178 in which
asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
is found instead of the normal
aspartic acid Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protei ...
. 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 The thalamus (: thalami; from Greek θάλαμος, "chamber") is a large mass of gray matter on the lateral wall of the third ventricle forming the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the ...
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.


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 The thalamus (: thalami; from Greek language, Greek Wikt:θάλαμος, θάλαμος, "chamber") is a large mass of gray matter on the lateral wall of the third ventricle forming the wikt:dorsal, dorsal part of the diencephalon (a division of ...
and a mild hypo-metabolism of the
cingulate cortex The cingulate cortex is a part of the brain situated in the medial aspect of the cerebral cortex. The cingulate cortex includes the entire cingulate gyrus, which lies immediately above the corpus callosum, and the continuation of this in the cin ...
. The extent of this symptom varies between two variations of the disease, these being those presenting methionine
homozygote Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...
s at codon 129 and methionine/valine
heterozygote Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...
s, 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.


Diagnosis

Diagnosis is based on symptoms and can be supported by a
sleep study A sleep study is a test that records the activity of the body during sleep. There are five main types of sleep studies that use different methods to test for different sleep characteristics and disorders. These include simple sleep studies, polysom ...
, a
PET scan Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in Metabolism, metabolic processes, and in other physiological activities including bloo ...
and
genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
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 An autopsy (also referred to as post-mortem examination, obduction, necropsy, or autopsia cadaverum) is a surgical procedure that consists of a thorough examination of a corpse by dissection to determine the cause, mode, and manner of deat ...
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. racco et al. Handb Clin Neurol 2018Mock 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 8FFDG-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. ortelli et al. Brain 2006/sup> The complexity and cost of this test currently impedes 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 Bovine spongiform encephalopathy (BSE), commonly known as mad cow disease, is an incurable and always fatal neurodegenerative disease of cattle. Symptoms include abnormal behavior, trouble walking, and weight loss. Later in the course of th ...
(BSE, also known as mad cow disease) in cattle and
chronic wasting disease Chronic wasting disease (CWD), sometimes called zombie deer disease, is a transmissible spongiform encephalopathy (TSE) affecting deer. TSEs are a family of diseases thought to be caused by misfolded proteins called prions and include simila ...
in American
deer A deer (: deer) or true deer is a hoofed ruminant ungulate of the family Cervidae (informally the deer family). Cervidae is divided into subfamilies Cervinae (which includes, among others, muntjac, elk (wapiti), red deer, and fallow deer) ...
and American elk in some areas of the United States and Canada, as well as
Creutzfeldt–Jakob disease Creutzfeldt–Jakob disease (CJD) is an incurable, always fatal neurodegenerative disease belonging to the transmissible spongiform encephalopathy (TSE) group. Early symptoms include memory problems, behavioral changes, poor coordination, visu ...
(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 Palliative care (from Latin root "to cloak") is an interdisciplinary medical care-giving approach aimed at optimizing quality of life and mitigating or reducing suffering among people with serious, complex, and often terminal illnesses. Man ...
. There is conflicting evidence over the use of sleeping pills, including
barbiturate Barbiturates are a class of depressant, depressant drugs that are chemically derived from barbituric acid. They are effective when used medication, medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological a ...
s, as a treatment for the disease. Symptoms of fatal familial insomnia may be treated with medications.
Clonazepam Clonazepam, sold under the brand name Klonopin among others, is a benzodiazepine medication used to prevent and treat anxiety disorders, seizures, bipolar mania, agitation associated with psychosis, obsessive–compulsive disorder (OCD), and ...
may be prescribed to treat muscle spasms, and
eszopiclone Eszopiclone, sold under the brand name Lunesta among others, is a nonbenzodiazepine medication used in the treatment of short-term and long-term insomnia. It holds the distinction of being one of the few FDA-approved hypnotic medications with ...
or
zolpidem Zolpidem, sold under the brand name Ambien among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and after beh ...
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 Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other non-essential amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine play ...
homozygosity at
codon Genetic code is a set of rules used by living cells to translate information encoded within genetic material (DNA or RNA sequences of nucleotide triplets or codons) into proteins. Translation is accomplished by the ribosome, which links prote ...
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 Neurology (from , "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the nervous system, which comprises the brain, the ...
/sleep expert Dr Ignazio Roiter received a patient at the
University of Bologna The University of Bologna (, abbreviated Unibo) is a Public university, public research university in Bologna, Italy. Teaching began around 1088, with the university becoming organised as guilds of students () by the late 12th century. It is the ...
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) ugaresi 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 7 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. edori 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 Meditation is a practice in which an individual uses a technique to train attention and awareness and detach from reflexive, "discursive thinking", achieving a mentally clear and emotionally calm and stable state, while not judging the meditat ...
, different stimulants and
hypnotics A hypnotic (from Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to induce sleep and to treat insomnia (sleeplessness). Th ...
and even complete
sensory deprivation Sensory deprivation or perceptual isolation is the deliberate reduction or removal of stimuli from one or more of the senses. Simple devices such as blindfolds or hoods and earmuffs can cut off sight and hearing, while more complex devices can ...
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 An autopsy (also referred to as post-mortem examination, obduction, necropsy, or autopsia cadaverum) is a surgical procedure that consists of a thorough examination of a corpse by dissection to determine the cause, mode, and manner of deat ...
revealed mild
atrophy Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), malnutrition, poor nourishment, poor circulatory system, circulation, loss of hormone, ...
of the frontal cortex and moderate atrophy of the
thalamus The thalamus (: thalami; from Greek language, Greek Wikt:θάλαμος, θάλαμος, "chamber") is a large mass of gray matter on the lateral wall of the third ventricle forming the wikt:dorsal, dorsal part of the diencephalon (a division of ...
. 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 Mepacrine, also called quinacrine or by the trade names Atabrine or Atebrin, is a medication with several uses. It is related to chloroquine and mefloquine. Although available from compounding pharmacies, as of August 2020 approved formulations ...
, and
amphotericin B Amphotericin B is an antifungal medication used for serious fungal infections and leishmaniasis. The fungal infections it is used to treat include mucormycosis, aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, and cryptococ ...
. , a study investigating
doxycycline Doxycycline is a Broad-spectrum antibiotic, broad-spectrum antibiotic of the Tetracycline antibiotics, tetracycline class used in the treatment of infections caused by bacteria and certain parasites. It is used to treat pneumonia, bacterial p ...
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 The thalamus (: thalami; from Greek language, Greek Wikt:θάλαμος, θάλαμος, "chamber") is a large mass of gray matter on the lateral wall of the third ventricle forming the wikt:dorsal, dorsal part of the diencephalon (a division of ...
, 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 The Eli and Edythe L. Broad Institute of MIT and Harvard (IPA: , pronunciation respelling: ), often referred to as the Broad Institute, is a biomedical and genomic research center located in Cambridge, Massachusetts, United States. The institu ...
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
biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
s to track the progression of prion disease in living people.


References


External links

* {{DEFAULTSORT:Fatal Familial Insomnia Neurodegenerative disorders Transmissible spongiform encephalopathies Unsolved problems in neuroscience Sleep disorders Rare diseases Sleeplessness and sleep deprivation