Fatal Familial Insomnia

Pierluigi Gambetti , Elio Lugaresi , in Encyclopedia of the Neurological Sciences, 2003

Genetics

Fatal familial insomnia is invariably associated with a mutation at codon (the unit of the gene that specifies i amino acrid) 178 of the PrP gene leading to the commutation of the amino acrid aspartic acid with asparagine and identified as D178N. However, the D178N mutation is likewise associated with a familial affliction that is quite different in clinical and pathological features from FFI and is identified as Creutzfeldt–Jakob disease with mutation at codon 178 (CJD 178) because it has a phenotype similar to that of the well-nigh mutual grade of sporadic human prion disease (Fig. 1). The association of two phenotypically distinct diseases with the same mutation, known as phenotypic heterogeneity, was unremarkably believed to result from the modification of the disease phenotype by environmental factors, another gene, or the paternal or maternal origin of the mutation. It was instead shown that although the pathogenic mutation is identical, FFI and CJD178 differ genetically at codon 129 of the PrP gene that in humans is the site of a common methionine/valine (G/V) polymorphism (i.eastward., in normal individuals codon 129 may specify either the M or the V amino acid in position 129 of the PrP). It was determined that all patients with FFI have codon M at position 129 of the mutated allele (ane copy of the cistron inherited from one of the 2 parents), whereas all patients with CJD178 have codon V in that position. Furthermore, since the other normal allele may have either the Yard or the V codon at position 129, patients may too be either G/Chiliad (homozygous) or M/V (heterozygous) at codon 129 when both alleles are considered. It has been observed that FFI has on boilerplate a shorter elapsing in homozygous (G/Chiliad) patients than in heterozygous (Grand/V) patients. Furthermore, homozygous and heterozygous FFI patients differ slightly in clinical and pathological features. Therefore, codon 129 plays a twofold role in determining the phenotypic heterogeneity of the D178N mutation: On the mutant allele it determines the phenotype (either FFI or CJD178) of the two diseases associated with the D178N mutation, and on the normal allele it specifies affliction duration (or severity) and some additional features of each of the two diseases. A similar machinery has been demonstrated in other familial prion diseases and might also play a role in other neurodegenerative weather.

Figure i. Diagram of the effect of the methionine/valine genotype at codon 129 on the phenotype of the illness associated with the D178N mutation of the prion protein gene. On the mutant allele, codon 129 Met/Val determines the bones disease phenotype. When the methionine codon is present on that allele, the patient develops FFI; when the valine codon is present, the patient develops CJD178. On the normal allele, codon 129 determines the zygosity of FFI and CJD178 patients. FFI patients homozygous and heterozygous at codon 129 take two methionine alleles or a methionine and a valine allele, respectively; homozygous and heterozygous CJD178 patients have two valine alleles or a valine and a methionine allele, respectively. Homozygous FFI patients take, on an boilerplate, a shorter disease duration; in CJD178 patients, the disease has a shorter course and as well starts before. Therefore, the normal allele codon 129 seems to touch on the severity of the disease in both FFI and CJD178. In FFI, codon 129 on the normal allele also affects the clinical presentation (see text).

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Transmissible Spongiform Encephalopathies

Ermias D. Belay , in International Encyclopedia of Public Health (Second Edition), 2017

Fatal Familial Insomnia

FFI patients accept predominant involvement of the thalamus, resulting in severe sleep disturbances, often with intractable insomnia, and autonomic nervous organization dysfunction, including abnormalities in temperature regulation, increased heart charge per unit, and hypertension. Pathologic examination of the brain from FFI patients consistently shows preferential interest of the thalamus with more severe neuronal loss and astrogliosis than seen in other brain regions. Although occasional sporadic fatal insomnia cases with no prion poly peptide gene mutation have been identified, FFI is primarily associated with codon 178 mutation, resulting in the substitution of aspartic acrid with asparagine in combination with methionine at codon 129 of the mutant allele. FFI patients take been reported from several European countries, Australia, Canada, Nihon, and the United States. The clinical signs and illness elapsing in FFI patients are influenced by the polymorphism at codon 129 of the nonmutant allele.

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Transmissible Spongiform Encephalopathies

E.D. Belay , L.B. Schonberger , in Encyclopedia of Virology (Third Edition), 2008

Fatal familial insomnia

FFI is a human prion disease with predominant involvement of the thalamus, resulting in a clinical phenotype characterized oftentimes by intractable insomnia and autonomic nervous organization dysfunction, including abnormalities in temperature regulation, increased center rate, and hypertension. The neuropathologic lesions are more astringent in the thalamus than other regions of the brain. FFI is primarily associated with a mutation at codon 178 of the prion protein cistron resulting in a substitution of aspartic acid with asparagine in combination with methionine at the polymorphic codon 129 of the mutant allele. Occasionally, sporadic FFI cases with no apparent mutation in the prion protein gene have been reported. FFI has been identified in Australia, Canada, Nippon, the US, and several European countries.

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Prion Protein

Diane Fifty. Ritchie , James W. Ironside , in Progress in Molecular Biology and Translational Science, 2017

4.iii.8 FFI

FFI is characterized by astringent thalamic gliosis and neuronal loss in the anterior thalamic nuclei and occasionally in other thalamic and hypothalamic nuclei. Spongiform change and disease-associated PrP accumulation in the thalamus are difficult to notice, only may be present in the entorhinal cortex or cerebellum. FFI is associated with the PRNP D178N-129M haplotype. The PRNP D178N mutation is also institute in some patients with genetic CJD, only in a D178N–129V haplotype. 2 Western blot assay in FFI shows a encephalon PrPres blazon 2A/B (Fig. 3).

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Human Prion Diseases

Laura Cracco , ... Pierluigi Gambetti , in Handbook of Clinical Neurology, 2018

Abstract

Fatal familial indisposition (FFI) and sporadic fatal insomnia (sFI), or thalamic grade of sporadic Creutzfeldt–Jakob disease MM2 (sCJDMM2T), are prion diseases originally named and characterized in 1992 and 1999, respectively. FFI is genetically determined and linked to a D178N mutation coupled with the M129 genotype in the prion protein gene ( PRNP) at chromosome 20. sFI is a phenocopy of FFI and probable its sporadic form. Both diseases are primarily characterized by progressive slumber damage, disturbances of autonomic nervous system, and motor signs associated with severe loss of nervus cells in medial thalamic nuclei. Both diseases harbor an abnormal disease-associated prion protein isoform, resistant to proteases with relative mass of nineteen kDa identified as resPrPTSE type 2. To date at to the lowest degree seventy kindreds affected by FFI with 198 members and 18 unrelated carriers along with 25 typical cases of sFI have been published. The D178N-129M mutation is idea to cause FFI by destabilizing the mutated prion poly peptide and facilitating its conversion to PrPTSE. The thalamus is the brain region first afflicted. A like mechanism triggered spontaneously may underlie sFI.

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Organizational Cell Biology

Thousand. Legname , K.East. Pischke , in Encyclopedia of Jail cell Biology, 2016

FFI

Fatal familial indisposition (FFI) is a rare autosomal dominant inherited prion disease. Information technology usually presents with progressive, severe insomnia, dysautonomia, and endocrine disturbances. FFI is virtually ever caused past PrP C mutations, but rare, sporadic cases have also been described, termed sporadic fatal insomnia (sFI). Disease onset usually occurs in the 5th and sixth decade of life and the mean duration of the disease is 18 months. Spongiform degeneration is rarely institute in FFI patients, but neuronal loss and gliosis, specifically within the thalamus, is common (Capellari et al., 2011; Pocchiari et al., 2004).

Nearly 100 cases of FFI in almost 40 families have been reported from Italian republic, Federal republic of germany, Republic of austria, Espana, Uk, France, Finland, the United states, Australia, Nihon, Cathay, and Morocco (Baldin et al., 2009).

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Prions and Prion Diseases of the Primal Nervous Arrangement (Transmissible Neurodegenerative Diseases)

Patrick J. Bosque , Kenneth L. Tyler , in Mandell, Douglas, and Bennett's Principles and Do of Infectious Diseases (Eighth Edition), 2015

Fatal Familial Indisposition

FFI first was reported as a homo disease in 1986, 117 although there is clinical and pathologic overlap between FFI and cases described earlier as "thalamic dementia." 118 In the early 1990s, the immunohistochemical detection of abnormal PrP and the subsequent recognition of a D178N mutation in PRNP marked FFI as a prion disease with unusual features. 119 The D178N mutation tin occur in 2 different PRNP allele forms, with either a methionine or a valine lawmaking for the polymorphic codon 129. The D178N/129M allele associates with FFI, whereas a syndrome more closely resembling typical sCJD occurs in patients conveying the D178N/129V allele. Although the commencement reports of FFI were all in Italian families, currently, at to the lowest degree 27 families with FFI accept been reported from the U.k., Europe, the United States, Finland, Australia, China, and Nihon. 120

In the typical course of FFI, patients develop indisposition equally a prominent and early complaint, forth with signs of autonomic hyperactivity (increased sweating, tearing, salivation, mild nocturnal hyperthermia, tachycardia, and hypertension). Motor disturbances develop later and can include ataxia, myoclonus, spasticity, hyperreflexia, and dysarthria. 119,120,121 Marked memory impairment is not prominent early on in the disease, although a delirium-similar hallucinosis may occur. The mean age of onset in FFI is 50 to 56 years, somewhat younger than in sCJD, only cases in patients equally young as 19 years and as old equally 83 years of historic period have been reported. 107,122-124 Series of patients with the FFI genotype describe substantial clinical heterogeneity. Ataxia and psychiatric signs, such as depression, apathy, or feet, are mutual initial complaints, and insomnia is not ever noted by the patient, family, or clinicians. 122,123 Polysomnography is a sensitive test for FFI, beingness abnormal in almost all cases, simply investigations take shown this is truthful for sCJD also. 125 In both forms of prion diseases, at that place are marked reductions or absence of both rapid eye movement (REM) and normal not-REM sleep.

Neuropathologic changes, including neuronal loss and reactive gliosis, are found consistently in the anterior ventral and mediodorsal nuclei of the thalamus, the inferior olives, with less prominent involvement of the cerebellar and cerebral cortex. 114,121,126 Immunostaining of brain fabric for PrPSc is positive, although the concentration of protein is 5 to x times less than that seen in sCJD.

As mentioned earlier, a rare sporadic form of homo prion disease presents with clinical and histopathologic features identical to those of FFI (desultory fatal insomnia [sFI]). 98 Both FFI and sFI can be transmitted to transgenic mice expressing wild-type human PrP. The clinical and histopathologic properties of the illness in these mice, every bit well as the biochemical properties of the PrPSc produced, are identical, and they are distinct from those of sCJD. 99 Thus, the prions associated with sFI and FFI are a singled-out strain, different from that which causes typical sCJD.

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Sleep Disorders

David Myland Kaufman MD , ... Marking J. Milstein Physician , in Kaufman's Clinical Neurology for Psychiatrists (Eighth Edition), 2017

Fatal Familial Indisposition

Fatal familial insomnia (FFI) consists of progressively severe insomnia, refractory to hypnotics, that appears on the average at l years of age. Like Creutzfeldt–Jakob disease (run into Affiliate vii), FFI is caused by a mutation of the prion protein factor (PRNP) that results in accumulation of abnormal prion poly peptide (PrPSc). Cognitive impairments, including inattentiveness, amnesia, sequencing problems, and confusion, develop and worsen along with the insomnia. Subsequently in their course, patients also develop hyperactive ANS activity (tachycardia, hyperhidrosis), endocrine abnormalities (elevated catecholamine and other hormone levels), and motor abnormalities (myoclonus, ataxia). FFI follows a relentless fatal form over half dozen to 36 months.

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Slumber and Neurologic Disorders

Richard B. Berry Dr. , in Fundamentals of Slumber Medicine, 2012

Other Neurodegenerative Disorders

Fatal Familial Insomnia

Fatal familial indisposition (FFI) is a familial autosomal ascendant prion disorder associated with the D178N mutation and methionine-methionine genotype at codon 129 in the prion poly peptide gene on chromosome 20. 40,41 Of annotation, the D178N mutation and valine-valine genotype at codon 129 are associated with familial Creutzfeldt-Jakob disease (CJD).

Topography of Degeneration

Methionine-methionine genotype at codon 129 produces dorsomedial and anteroventral thalamic dysfunction, whereas the valine-valine genotype of CJD is associated with more general cortical involvement.

FFI Manifestations

FFI manifestations include insomnia, dementia, ataxia, dysarthria, dysautonomia, hallucinations, and hypersomnolence. The duration from onset to death varies from a few months to 4 years.

Diagnosis

The International Classification of Sleep Disorders, 2d edition (ICSD-2), diagnostic criteria for FFI are listed in Box 31–10. The PSG in FFI reveals severe disruption of the slumber-wake cycle, loss of slumber spindles, reduction in stage N3 and phase R, likewise as reduced sleep efficiency. REM sleep without atonia tin can occur.

Positron Emission Tomography Browse

Positron emission tomography (PET) reveals nearly absent or very depression activity of the thalamus.

Summary

FFI should be considered in any patient with prominent sleep-wake disturbance and dementia. Handling is supportive.

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Clinical Syndromes and Cardinal Features of Infectious Diseases: Approach to Diagnosis and Initial Management

Leonel T. Takada , Michael D. Geschwind , in Principles and Do of Pediatric Infectious Diseases (Fourth Edition), 2012

Familial Fatal Insomnia (FFI)

Fatal familial insomnia (FFI) is a rare disorder that ordinarily manifests with progressive, severe indisposition and dysautonomia, with motor and cognitive problems actualization afterward. Onset commonly occurs in the 5th and 6th decade (but has been reported in individuals as immature as nineteen years 77 ) and duration is around ane to 1.five years. ix Although brain MRI usually is normal, FDG-PET imaging reveals thalamic and cingulate hypometabolism. Both sporadic (a subtype of sCJD) and familial forms of fatal insomnia are recognized. FFI is acquired by a single PRNP point mutation, D178N, with codon 129M on the same chromosome (cis) (patients with D178N-129V usually nowadays equally fCJD). 82 Neuropathology of FFI is primarily characterized by thalamic gliosis and neuronal loss. 9,49

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