Sporadic Fatal Insomnia in Europe: Phenotypic Features and Diagnostic Challenges

Abu‐Rumeileh, Samir; Redaelli, Veronica; Baiardi, Simone; Mackenzie, Graeme; Windl, Otto; Ritchie, Diane; Didato, Giuseppe; Hernández‐Vara, Jorge; Rossi, Marcello; Capellari, Sabina; Imperiale, Daniele; Rizzone, Mario Giorgio; Belotti, Alessia; Sorbi, Sandro; Rozemüller, Annemieke; Cortelli, Pietro; Gelpí, Ellen; Will, Robert; Zerr, Inga; Giaccone, Giorgio; Parchi, Piero

doi:10.1002/ana.25300

Cited by 31 publications

(29 citation statements)

References 47 publications

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“…sFI-I48 was previously described as the MM2-thalamic form with widespread cortical pathology ( Hirose et al , 2006 ), and sFI-T00/06 showing partial SC was previously reported as a thalamic variant of sCJD with severe brain atrophy and plaque-like PrP deposition ( Yamashita et al , 2001 ). These results demonstrated that the combination of SC and OD was also commonly observed in the brains of patients with sFI, as previously reported ( Abu-Rumeileh et al , 2018 ).…”

Section: Resultssupporting

confidence: 91%

Two distinct prions in fatal familial insomnia and its sporadic form

Takeuchi

Mohri

Kai

et al. 2019

Brain Communications

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Fatal familial insomnia is a genetic prion disease, which is associated with the aspartic acid to asparagine substitution at codon 178 of the prion protein gene. Although the hallmark pathological feature is thalamic and olivary degeneration, there is a patient with an atypical fatal familial insomnia without the hallmark feature. The cause of the pathological variability is unclear. We analysed a Japanese fatal familial insomnia kindred and compared one atypical clinicopathological fatal familial insomnia phenotype case and typical fatal familial insomnia phenotype cases with transmission studies using multiple lines of knock-in mice and with protein misfolding cyclic amplification. We also analysed the transmissibility and the amplification properties of sporadic fatal insomnia. Transmission studies revealed that the typical fatal familial insomnia with thalamic and olivary degeneration showed successful transmission only using knock-in mice expressing human–mouse chimeric prion protein gene. The atypical fatal familial insomnia with spongiform changes showed successful transmission only using knock-in mice expressing bank vole prion protein gene. Two sporadic fatal insomnia cases with thalamic and olivary degeneration showed the same transmissibility as the typical fatal familial insomnia phenotype. Interestingly, one sporadic fatal insomnia case with thalamic/olivary degeneration and spongiform changes showed transmissibility of both the typical and atypical fatal familial insomnia phenotypes. Protein misfolding cyclic amplification could amplify both typical fatal familial insomnia cases and sporadic fatal insomnia cases but not the atypical fatal familial insomnia phenotype or other sporadic Creutzfeldt–Jakob disease subtypes. In addition to clinical findings and neuropathological features, the transmission properties and the amplification properties were different between the typical and atypical fatal familial insomnia phenotypes. It is suggested that two distinct prions were associated with the diversity in the fatal familial insomnia phenotype, and these two prions could also be detected in sporadic fatal insomnia.

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Section: Resultssupporting

confidence: 91%

Two distinct prions in fatal familial insomnia and its sporadic form

Takeuchi

Mohri

Kai

et al. 2019

Brain Communications

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“…Similarly, in a recent series of European sCJDMM2T, the two subjects with the longest disease duration (54 and 96 months) showed severe spongiform change in the striatum, which is usually relatively spared in this subtype, and one of them also demonstrated an atypical pattern of PrP staining characterized by sparse, small plaque‐like deposits in the cerebral cortex . Thus, in long‐lasting sCJDMM2T cases, spongiform change may not be limited to the cerebral cortex and PrP Sc aggregates may form small plaques in addition to the synaptic/fine granular pattern.…”

Section: Phenotypic Spectrum and Classification Of Disease Subtypesmentioning

confidence: 83%

“…The MM(V)1 subtype includes both MM1 and MV1 cases given that they are phenotypically indistinguishable, whereas the MM2 group comprises two subtypes with distinctive histopathological features and topographical distribution of lesions mainly affecting the cerebral cortex (MM2‐Cortical or MM2C) or the thalamus (MM2‐Thalamic or MM2T). The latter subtype is also known as the sporadic form of FI . It is also noteworthy that about 35% of sCJD cases show the co‐occurrence of PrP Sc types 1 and 2, an intriguing and still unexplained phenomenon that is more often observed in subjects carrying MM at codon 129 than in the other genotypes .…”

Section: Phenotypic Spectrum and Classification Of Disease Subtypesmentioning

confidence: 99%

Recent advances in the histo‐molecular pathology of human prion disease

et al. 2019

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Prion diseases are progressive neurodegenerative disorders affecting humans and other mammalian species. The term prion, originally put forward to propose the concept that a protein could be infectious, refers to PrP Sc , a misfolded isoform of the cellular prion protein (PrP C ) that represents the pathogenetic hallmark of these disorders. The discovery that other proteins characterized by misfolding and seeded aggregation can spread from cell to cell, similarly to PrP Sc , has increased interest in prion diseases. Among neurodegenerative disorders, however, prion diseases distinguish themselves for the broader phenotypic spectrum, the fastest disease progression and the existence of infectious forms that can be transmitted through the exposure to diseased tissues via ingestion, injection or transplantation. The main clinicopathological phenotypes of human prion disease include Creutzfeldt-Jakob disease, by far the most common, fatal insomnia, variably protease-sensitive prionopathy, and Gerstmann-Sträussler-Scheinker disease. However, clinicopathological manifestations extend even beyond those predicted by this classification. Because of their transmissibility, the phenotypic diversity of prion diseases can also be propagated into syngenic hosts as prion strains with distinct characteristics, such as incubation period, pattern of PrP Sc distribution and regional severity of histopathological changes in the brain. Increasing evidence indicates that different PrP Sc conformers, forming distinct ordered aggregates, encipher the phenotypic variants related to prion strains. In this review, we summarize the most recent advances concerning the histo-molecular pathology of human prion disease focusing on the phenotypic spectrum of the disease including co-pathologies, the characterization of prion strains by experimental transmission and their correlation with the physicochemical properties of PrP Sc aggregates.

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“…* Ratio between diglycosylated and unglycosylated PrP Sc fragment; ° Lacks diglycosylated PrP Sc . Data summarized in the Table are taken from the following studies: disease frequency [32,60,69], disease duration [32,60,69,70], T50 [68], PK-resistance ED50, glycosylation and aggregation ratios [67], attack-rate and incubation time [71,72,73,74,75,76,77,78]. NA, not available; ND, not defined.…”

Section: Figurementioning

confidence: 99%

Understanding Prion Strains: Evidence from Studies of the Disease Forms Affecting Humans

Rossi

Baiardi

Parchi

2019

Viruses

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Prion diseases are a unique group of rare neurodegenerative disorders characterized by tissue deposition of heterogeneous aggregates of abnormally folded protease-resistant prion protein (PrPSc), a broad spectrum of disease phenotypes and a variable efficiency of disease propagation in vivo. The dominant clinicopathological phenotypes of human prion disease include Creutzfeldt–Jakob disease, fatal insomnia, variably protease-sensitive prionopathy, and Gerstmann–Sträussler–Scheinker disease. Prion disease propagation into susceptible hosts led to the isolation and characterization of prion strains, initially operatively defined as “isolates” causing diseases with distinctive characteristics, such as the incubation period, the pattern of PrPSc distribution, and the regional severity of neuropathological changes after injection into syngeneic hosts. More recently, the structural basis of prion strains has been linked to amyloid polymorphs (i.e., variant amyloid protein conformations) and the concept extended to all protein amyloids showing polymorphic structures and some evidence of in vivo or in vitro propagation by seeding. Despite the significant advances, however, the link between amyloid structure and disease is not understood in many instances. Here we reviewed the most significant contributions of human prion disease studies to current knowledge of the molecular basis of phenotypic variability and the prion strain phenomenon and underlined the unsolved issues from the human disease perspective.

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Sporadic Fatal Insomnia in Europe: Phenotypic Features and Diagnostic Challenges

Cited by 31 publications

References 47 publications

Two distinct prions in fatal familial insomnia and its sporadic form

Two distinct prions in fatal familial insomnia and its sporadic form

Recent advances in the histo‐molecular pathology of human prion disease

Understanding Prion Strains: Evidence from Studies of the Disease Forms Affecting Humans

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