Fatal familial insomnia
Encyclopedia
Fatal familial insomnia (FFI) is a very rare autosomal
dominant inherited
prion
disease
of the brain
. It is almost always caused by a mutation to the protein PrPC, but can also develop spontaneously in patients with a non-inherited mutation variant called sporadic fatal insomnia (SFI). FFI is an incurable disease, involving progressively worsening insomnia, which leads to hallucinations, delirium, and confusional states like that of dementia. The average survival span for patients diagnosed with FFI 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% chance of inheriting it and developing the disease. The first recorded victim was an Italian man, deceased in Venice
in the year 1765.
carry a mutation at codon 178 of the prion protein gene. FFI is invariably linked to the presence of the methionine
codon at position 129 of the mutant allele, whereas CJD 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 a asparagine (N) is found instead of the normal aspartic acid (D). This has to be accompanied with a methionine at position 129."
The disease has four stages, taking 7 to 18 months to run its course:
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.
is so far unsuccessful. While it is not currently possible to reverse the underlying illness, there is some evidence that treatments that focus upon the symptoms can improve quality of life.
Several cases have proven that sleeping pills and barbiturates do not help; they make FFI worse and actually speed up the disease.
One of the most notable cases is that of Michael Corke, a music teacher from Chicago, Illinois. He suddenly began to have trouble sleeping not long after his 40th birthday in 1991, and his health and state of mind quickly deteriorated as his sleeplessness grew worse. Eventually, he couldn't sleep at all, and he was soon admitted to hospital. Doctors there weren't sure what was wrong with him, initially diagnosing Multiple Sclerosis
; in a bid to send him to sleep in the later stages of the disease, physicians induced a coma with the use of sedatives, but they found that his brain still failed to shut down. Corke died in 1992 a month before his 41st birthday, by which time he had gone without sleep for six months.
In the late 2000s, a mouse model was made for FFI. These mice express 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 people with FFI.
) such as kuru
, bovine spongiform encephalopathy
(BSE, also known as "mad cow disease") in cows, 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 via direct contact with infected tissue, such as from eating infected tissue, transfusion or transplantation; new research now suggests that prion diseases can be transmitted via aerosols, but that the general public is not at risk of airborne infection.
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
dominant inherited
Dominance relationship
Dominance in genetics is a relationship between two variant forms of a single gene, in which one allele masks the effect of the other in influencing some trait. In the simplest case, if a gene exists in two allelic forms , three combinations of alleles are possible: AA, AB, and BB...
prion
Prion
A prion is an infectious agent composed of protein in a misfolded form. This is in contrast to all other known infectious agents which must contain nucleic acids . The word prion, coined in 1982 by Stanley B. Prusiner, is a portmanteau derived from the words protein and infection...
disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
of the brain
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...
. It is almost always caused by a mutation to the protein PrPC, but can also develop spontaneously in patients with a non-inherited mutation variant called sporadic fatal insomnia (SFI). FFI is an incurable disease, involving progressively worsening insomnia, which leads to hallucinations, delirium, and confusional states like that of dementia. The average survival span for patients diagnosed with FFI 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% chance of inheriting it and developing the disease. The first recorded victim was an Italian man, deceased in Venice
Venice
Venice is a city in northern Italy which is renowned for the beauty of its setting, its architecture and its artworks. It is the capital of the Veneto region...
in the year 1765.
The prion
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 Creutzfeldt-Jakob diseaseCreutzfeldt-Jakob disease
Creutzfeldt–Jakob disease or CJD is a degenerative neurological disorder that is incurable and invariably fatal. CJD is at times called a human form of mad cow disease, given that bovine spongiform encephalopathy is believed to be the cause of variant Creutzfeldt–Jakob disease in humans.CJD...
carry a mutation at codon 178 of the prion protein gene. FFI is invariably linked to the presence of the methionine
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
codon at position 129 of the mutant allele, whereas CJD is linked to the presence of the valine
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
codon at that position. "The disease is where there is a change of amino acid at position 178 when a asparagine (N) is found instead of the normal aspartic acid (D). This has to be accompanied with a methionine at position 129."
Presentation
The age of onset is variable, ranging from 18 to 60, with an average of 50. However the disease tends to prominently occur in later years, primarily following childbirth. The disease can be detected prior to onset by genetic testing. Death usually occurs between 7 and 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, taking 7 to 18 months to run its course:
- The patient suffers increasing insomniaInsomniaInsomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, resulting in panic attackPanic attackPanic attacks are periods of intense fear or apprehension that are of sudden onset and of relatively brief duration. Panic attacks usually begin abruptly, reach a peak within 10 minutes, and subside over the next several hours...
s, paranoiaParanoiaParanoia [] is a thought process believed to be heavily influenced by anxiety or fear, often to the point of irrationality and delusion. Paranoid thinking typically includes persecutory beliefs, or beliefs of conspiracy concerning a perceived threat towards oneself...
, and phobiaPhobiaA phobia is a type of anxiety disorder, usually defined as a persistent fear of an object or situation in which the sufferer commits to great lengths in avoiding, typically disproportional to the actual danger posed, often being recognized as irrational...
s. This stage lasts for about four months. - HallucinationHallucinationA hallucination, in the broadest sense of the word, is a perception in the absence of a stimulus. In a stricter sense, hallucinations are defined as perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid,...
s and panic attacks become noticeable, continuing for about five months. - Complete inability to sleepSleepSleep is a naturally recurring state characterized by reduced or absent consciousness, relatively suspended sensory activity, and inactivity of nearly all voluntary muscles. It is distinguished from quiet wakefulness by a decreased ability to react to stimuli, and is more easily reversible than...
is followed by rapid loss of weightWeightIn science and engineering, the weight of an object is the force on the object due to gravity. Its magnitude , often denoted by an italic letter W, is the product of the mass m of the object and the magnitude of the local gravitational acceleration g; thus:...
. This lasts for about three months. - DementiaDementiaDementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
, during which the patient becomes unresponsive or mute over the course of six months. This is the final progression of the disease, after which deathDeathDeath is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
follows.
Other symptoms include profuse sweating, pinpoint pupils
Miosis
Miosis is the constriction of the pupil of the eye to two millimeters or less...
, the sudden entrance into menopause
Menopause
Menopause is a term used to describe the permanent cessation of the primary functions of the human ovaries: the ripening and release of ova and the release of hormones that cause both the creation of the uterine lining and the subsequent shedding of the uterine lining...
for women and impotence for men, neck stiffness, and elevation of blood pressure and heart rate. Constipation is common as well.
Treatment
There is no cure or treatment for FFI. Gene therapyGene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...
is so far unsuccessful. While it is not currently possible to reverse the underlying illness, there is some evidence that treatments that focus upon the symptoms can improve quality of life.
Several cases have proven that sleeping pills and barbiturates do not help; they make FFI worse and actually speed up the disease.
One of the most notable cases is that of Michael Corke, a music teacher from Chicago, Illinois. He suddenly began to have trouble sleeping not long after his 40th birthday in 1991, and his health and state of mind quickly deteriorated as his sleeplessness grew worse. Eventually, he couldn't sleep at all, and he was soon admitted to hospital. Doctors there weren't sure what was wrong with him, initially diagnosing Multiple Sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
; in a bid to send him to sleep in the later stages of the disease, physicians induced a coma with the use of sedatives, but they found that his brain still failed to shut down. Corke died in 1992 a month before his 41st birthday, by which time he had gone without sleep for six months.
In the late 2000s, a mouse model was made for FFI. These mice express 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
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
, and early deaths, similar to people with FFI.
Related conditions
There are other diseases involving the mammalian prion. Some are transmissible (TSEsTransmissible spongiform encephalopathy
Transmissible spongiform encephalopathies , also known as prion diseases, are a group of progressive conditions that affect the brain and nervous system of many animals, including humans. According to the most widespread hypothesis they are transmitted by prions, though some other data suggest an...
) such as kuru
Kuru (disease)
Kuru is an incurable degenerative neurological disorder that is a type of transmissible spongiform encephalopathy, caused by a prion found in humans...
, bovine spongiform encephalopathy
Bovine spongiform encephalopathy
Bovine spongiform encephalopathy , commonly known as mad-cow disease, is a fatal neurodegenerative disease in cattle that causes a spongy degeneration in the brain and spinal cord. BSE has a long incubation period, about 30 months to 8 years, usually affecting adult cattle at a peak age onset of...
(BSE, also known as "mad cow disease") in cows, and chronic wasting disease
Chronic wasting disease
Chronic wasting disease is a transmissible spongiform encephalopathy of mule deer, whitetailed deer, elk , and moose. TSEs are caused by unusual infectious agents known as prions. To date, CWD has been found mainly in cervids...
in American deer
Deer
Deer are the ruminant mammals forming the family Cervidae. Species in the Cervidae family include white-tailed deer, elk, moose, red deer, reindeer, fallow deer, roe deer and chital. Male deer of all species and female reindeer grow and shed new antlers each year...
and American elk
Elk
The Elk is the large deer, also called Cervus canadensis or wapiti, of North America and eastern Asia.Elk may also refer to:Other antlered mammals:...
in some areas of the United States and Canada, as well as Creutzfeldt-Jakob disease
Creutzfeldt-Jakob disease
Creutzfeldt–Jakob disease or CJD is a degenerative neurological disorder that is incurable and invariably fatal. CJD is at times called a human form of mad cow disease, given that bovine spongiform encephalopathy is believed to be the cause of variant Creutzfeldt–Jakob disease in humans.CJD...
(CJD). Until recently prion diseases were only thought to be transmissible via direct contact with infected tissue, such as from eating infected tissue, transfusion or transplantation; new research now suggests that prion diseases can be transmitted via aerosols, but that the general public is not at risk of airborne infection.