Biological Sciences
Fatal Familial Insomnia
Fatal Familial Insomnia is a rare genetic disease that affects the brain and causes progressive insomnia, leading to hallucinations, delirium, and eventually death. It is caused by a mutation in the PRNP gene, which leads to the accumulation of abnormal proteins in the brain. There is currently no cure for this disease.
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5 Key excerpts on "Fatal Familial Insomnia"
- Paul Shaw, Mehdi Tafti, Michael J. Thorpy(Authors)
- 2013(Publication Date)
- Cambridge University Press(Publisher)
With respect to Fatal Familial Insomnia (FFI), neurode- generation and lesions of the brainstem, hypothalamus and thalamus, are also major genetically driven targets that may lead to insomnia [16,37]. Fatal Familial Insomnia (FFI) FFI is a very rare prion disease clinically characterized by inability to sleep, dysautonomia and motor dis- turbances, rapidly leading to death [37]. FFI is the first sleep disorder for which a gene mutation has been identified, a point mutation (codon 178) in the prion protein gene (PRP) on chromosome 20 and rarely a mutation on codon 200 [37,38]. The same mutations are found in certain forms of dementia of the Creutzfeldt–Jakob type, but the polymorphic codon 129 appears to determine fatal insomnia phenotype expression versus Creutzfeldt–Jakob [38]. The major sleep features of FFI include a progressive reduction of total sleep time, an early disappearance of sleep spindles, a loss of slow-wave sleep, and the disintegration of the cyclic organization of sleep [38]. Interestingly, normal relatives of FFI patients who are carriers of the codon 178 mutation have a normal sleep while genotype at polymorphic codon 129 affects spindle and slow-wave activities independent from codon 178 [39]. Moreover, phenotypic and neuropatho- logic variabilities have been described recently between FFI homozygotes and heterozygotes at polymorphic codon 129, with a progressive disturbance of sleep clinically apparent in homozygous forms only [38]. The abnormal form of the prion protein, resistant to protease, is implicated in a group of disorders of the central nervous system (spongiform encepha- lopathies) where spongiform degeneration is observed with more or less focalized neuronal atrophy [38]. A severe neuronal loss and astrogliosis were found in the mediodorsal thalamic nuclei in association with relatively modest amounts of abnormal prion protein in FFI patients.
eBook - PDF- Angela L. Williams(Author)
- 2019(Publication Date)
- Omnigraphics(Publisher)
In very rare cases of Fatal Familial Insomnia, the cause is sporadic, meaning there is not a change in the PRNP gene. As of 2016, there have only been 24 reported cases of sporadic fatal familial insom-nia. Sporadic FFI occurs when some of a person’s normal PrP (prion 157 Fatal Familial Insomnia protein) spontaneously changes into the abnormal shape that causes Fatal Familial Insomnia, and then somehow changes the shape of PrP in other neurons in a chain reaction. Inheritance of Fatal Familial Insomnia In most cases, a person with Fatal Familial Insomnia has inherited the genetic change from a parent with Fatal Familial Insomnia. In order to have Fatal Familial Insomnia, a person only needs one copy of their PRNP gene to carry the specific genetic change (mutation) that causes FFI. In other words, a person only needs to inherit the genetic change from one parent. In genetic terms, this is called autosomal dominant inheritance. In rare cases, Fatal Familial Insomnia may result from a de novo (new) change in the PRNP gene, however, it is not known how often a new mutation is the cause of Fatal Familial Insomnia. New mutations can happen during the making of the egg or the sperm. A person that has the genetic change that causes FFI has a 50-per-cent chance with each pregnancy of passing along the changed gene to offspring. In the rare sporadic cases of Fatal Familial Insomnia, the disease is not inherited from either parent and cannot be passed down to their children. Prognosis for Fatal Familial Insomnia Presently, after symptoms of FFI begin, the disease usually causes death within 12 to 18 months, with a range of a few months to several years. As research continues, however, it is hoped that a treatment or even a cure will be developed that will dramatically change the outlook for people who have Fatal Familial Insomnia. 159 Chapter 21 Insomnia Insomnia is one of the most commonly reported sleep problems.
eBook - ePub- Pasquale Montagna, Sudhansu Chokroverty(Authors)
- 2012(Publication Date)
- Elsevier(Publisher)
These pathogenic problems notwithstanding, the “(prion) protein only” hypothesis has represented a remarkable reversal of the “nucleic acid only” paradigm for infectious diseases, as prions are thought to be devoid of nucleic acid and infectivity in prion diseases resides within the prion protein itself. The argument that this “prion protein only” mechanism could not account for the variable features of the clinical diseases and infectivity experiments collapsed when it was shown that infectious prions come in different strains according to the conformational species of a particular prion encoded by the sequence of the PrP gene of the infected animal. Thus, the “prion protein only” hypothesis is also able to account for the variety of the pathological and clinical features found in the different prion diseases, which had previously been thought impossible to explain without the help of information from nucleic acids.Familial Fatal Insomnia
Clinical features
FFI was first identified in 1986 in an Italian family as an autosomally dominant transmitted disease characterized by peculiar alterations in sleep and autonomic functions, and in which neuropathological examination disclosed prominent thalamic and inferior olivary changes (Lugaresi et al., 1986 ). FFI is a disease with onset usually in mid life: mean age at onset is 51 years, but the onset may range from 36 to 62 years. FFI affects both sexes equally, leading to death within a mean disease course of 18 months (range 8–72 months) (Lugaresi et al., 1986 ; Montagna et al., 1998 ). Two different disease courses are described, and attributed to the effects of the 129 PRNP codon polymorphism, which seems to modulate not only the disease duration but also the clinical features (see below); patients may have a short (less than 11 months; mean 9.1 months) or a prolonged (more than 11 months, mean 30.8 months) disease duration.FFI was recognized as a genetically transmitted prion disease in 1992 (Medori et al., 1992a , b ) and represents the third most frequent genetic prion disease. It has been reported worldwide, and its clinical and pathological features remain comparable in populations with different genetic backgrounds (Nagayama et al., 1996 ; Almer et al., 1999 ; Harder et al., 1999 ; Tabernero et al., 2000
eBook - PDF- Antonio Culebras(Author)
- 2007(Publication Date)
- CRC Press(Publisher)
Interestingly, there are at least three neurological conditions [Fatal Familial Insomnia (FFI), Morvan’s chorea (MC), and delirium tremens (DT)] in which the inability to sleep is typically associated with motor and sympathergic overactiva-tion. Agrypnia excitata (AE) is the term which aptly defines this generalized overactivation syndrome (57,58). The FFI is clinically characterized by apathy (attention deficit and indifference to surroundings) and an inability to sleep (agrypnia) accompanied by enacted dreams (gestures consistent with the context of a dream), sympathetic hyperactivity (profuse perspiration, tachycardia, hypertension, mild fever, etc.), and motor signs (ataxia, dysarthria, and myoclonus), and pathologically by selective degeneration of the anteroventral and mediodorsal thalamic nuclei (59). The FFI is an autosomal dominant prion disease linked to a point mutation at codon 178 of the prion protein gene at chromosome 20, in conjuction with methionine in the methionine / valine polymorphic position 129 on the mutant allele. Around 30 FFI kindreds have been described to date in addition to nine sporadic (nongenetic) cases [sporadic fatal insomnia (SFI)] (60). The FFI starts at a mean age of 51 + 7 years (standard deviation), and disease duration varies from eight months to seven years. The disease course is relatively short (9–10 months as a mean) in patients who are methionine – methionine homo-zygous at codon 129 of the prion protein gene, whereas heterozygous patients (expressing valine at codon 129 on the nonmutated allele) have a relatively long disease duration (30 months as a mean) (60). The sleep disorder, documented by detailed polysomnographic studies, com-prises an early disappearance of spindles and delta sleep which, markedly reduced from disease onset, disappear completely in the advanced stages of the disease.
eBook - PDF- Gayle Greene(Author)
- 2008(Publication Date)
- University of California Press(Publisher)
7 per-cent of 77 primary insomniacs. In both studies, the mother is the family member most frequently affected, and in both studies, when the insomnia THE BRAIN OF AN INSOMNIAC 131 is familial, it tends to come on earlier and not to be “psychiatric.” These findings are suggestive, though they still do not tell us whether the fam-ily influence is genetic or environmental. Genetic studies are needed to do that. “The sleep disorders field is a bit late in doing genetic studies,” says Emmanuel Mignot, the Stanford researcher who isolated the gene for ca-nine narcolepsy. “Other fields have done much more.” But it is moving fast. Mignot traced canine narcolepsy to a single mutation that renders the receptor for hypocretin nonfunctional. Narcolepsy in humans is not so simple. It may run in families, but it usually does not; it doesn’t come on until the second or third decade of a person’s life, and even when an identical twin is affected, the other twin, in 75 percent of the cases, is not. Researchers think that several genes may contribute to susceptibility, but the disorder also needs an environmental trigger. Researchers speculate that an autoimmune process may cause degeneration of the hypocretin-containing neurons in the hypothalamus, mimicking alterations caused by mutations. Fatal Familial Insomnia is the first sleep disorder for which a gene was identified. This is a rare neurodegenerative disease (about sixty cases worldwide) which is, as the name says, familial, and is also, as the name says, fatal. With other sleep disorders, like sleepwalking and sleep-talking, familial evidence is arrived at by family histories. “If you have two par-ents who sleepwalk, there’s a 60 percent chance that you will too,” says Clete Kushida, director of the Stanford University Center for Human Sleep Research.
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