A subtype of sporadic prion disease mimicking fatal familial insomnia

Division of Neuropathology, Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Neurology (Impact Factor: 8.3). 07/1999; 52(9):1757-63. DOI: 10.1212/WNL.52.9.1757
Source: PubMed

ABSTRACT To establish a variant of sporadic prion disease as the sporadic form of fatal familial insomnia (FFI).
FFI is a recently described prion disease characterized clinically by severe sleep impairment, dysautonomia, and motor signs, and pathologically by atrophy of thalamic nuclei, especially the medial dorsal and anterior ventral, and of the inferior olive. FFI is linked to the D178N mutation coupled with the methionine codon at position 129 in the prion protein gene (PRNP). It is also identified by the properties of the abnormal prion protein (PrP(Sc)), which has the relative molecular mass of 19 kDa, corresponding to the so-called type 2, and a marked underrepresentation of the unglycosylated form relative to the diglycosylated and monoglycosylated forms.
Clinical, pathologic, PrP(Sc), and PRNP data from 5 subjects with a sporadic prion disease phenotypically similar to FFI were collected and analyzed.
All 5 subjects had a disease clinically similar and histopathologically virtually identical to FFI. PrP(Sc) type 2 was present in all subjects in amount and distribution similar to those of FFI. However, the PrP(Sc) did not show the striking underrepresentation of the unglycosylated isoform of the protein that is characteristic of FFI. Moreover, none of the subjects had the D178N PRNP mutation but all were homozygous for methionine at codon 129.
This condition is likely to represent the sporadic form of FFI and the term "sporadic fatal insomnia" is proposed.

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    • "However, this is unlikely, because: (i) the PrP Sc from both cases were enriched by immuno-affinity column, and similar amounts of PrP Sc were loaded onto the two-dimensional gel; and (ii) when PrP Sc from the hippocampus and thalamus were compared with that from the frontal cortex of sFI, no major differences were detected in their two-dimensional profiles. As indicated in previous studies, thalamus contains much more PrP Sc in sFI (Parchi et al. 1999a; Montagna et al. 2003). "
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    ABSTRACT: The phenotype of human prion diseases is influenced by the prion protein (PrP) genotype as determined by the methionine (M)/valine (V) polymorphism at codon 129, the scrapie PrP (PrPSc) type and the etiology. To gain further insight into the mechanisms of phenotype determination, we compared two-dimensional immunoblot profiles of detergent insoluble and proteinase K-resistant PrP species in a type of sporadic Creutzfeldt-Jakob disease (sCJDMM2), variant CJD (vCJD) and sporadic fatal insomnia (sFI). Full-length and truncated PrP forms present in the insoluble fractions were also separately analyzed. These three diseases were selected because they have the same M/M PrP genotype at codon 129 and the same type 2 PrPSc, but different etiologies, also sCJDMM2 and sFI are sporadic, whereas vCJD is acquired by infection. We observed minor differences in the PrP detergent-insoluble fractions between sCJDMM2 and vCJD, although both differ in the corresponding fractions from sFI. We detected more substantial heterogeneity between sCJDMM2 and vCJD in the two-dimensional blots of the proteinase K-resistant PrP fraction suggesting that different PrP species are selected for conversion to proteinase K-resistant PrP in sCJDMM2 and vCJD. These differences are mostly, but not exclusively, due to variations in the type of the N-linked glycans. We also show that the over-representation of the highly glycosylated forms distinctive of the proteinase K-resistant PrPSc of vCJD in one-dimensional blots is due to differences in both the amount and the natures of the glycans. Overall, these findings underline the complexity of phenotypic determination in human prion diseases.
    Journal of Neurochemistry 02/2005; 92(1):132-42. DOI:10.1111/j.1471-4159.2004.02859.x · 4.24 Impact Factor
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    • "The widespread geographical distribution, single cases in each affected flock and the lack of genetic evidence suggests that Nor98 could possibly be a spontaneous/sporadic prion disease. In this regard it is noteworthy that similar to the Nor98/GSS comparison, sporadic fatal insomnia (sFI) show all the hallmarks of familial fatal insomnia (FFI) but lack the D178N substitution that is always associated with FFI (Mastrianni et al., 1999; Montagna, et al., 2003; Pan et al., 2001; Parchi et al., 1999; Piao et al., 2005; Scaravilli et al., 2000; Watts, Balachandran & Westaway, 2006). "
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    ABSTRACT: Transmissible spongiform encephalopathies (TSEs) are also known as prion diseases. The unusual infectious agent is composed largely, if not entirely, of a proteinase resistant aberrantly folded isoform of the prion protein (PrPSc). PrPSc, through an unknown mechanism, is believed to impose its aberrant conformation onto the host-encoded cellular prion protein, PrPC. The infectious particle is designated a "prion", an acronym for proteinaceous infectious particle, to distinguish it from conventional pathogens such as viruses and bacteria. The essential role of PrPC in the pathogenesis of prion diseases motivated the detailed study of the cellular processing, turnover and release of bovine PrPC (boPrPC) performed in this thesis. BoPrPC was found to be subjected to two distinct proteolytic cleavage events, generating an N-terminal and a C-terminal boPrPC fragment. Both PrP fragments were released from the cell. Moreover, in normal bovine brain a C-terminal fragment was found, suggesting that similar proteolytic processing events occur in vivo. The finding that boPrPC in addition to a protease-mediated release also was released in association with exosomes, provide important information in relation to functional aspects of PrPC and possible roles of exosome-associated PrP in pathogenesis of prion diseases. Taken together, these results indicate that release of boPrPC from cells represent an important step in the normal cellular processing of boPrPC. Nor98 is a recently recognised prion disease in sheep. The molecular characterization of the Nor98 prion showed that the unique PK-resistant PrP fragments present in Nor98-affected sheep display striking similarities to those reported from individuals affected by the human prion disorder Gerstmann-Sträussler-Scheinker syndrome (GSS). Interestingly, GSS is always associated with amino acid substitutions in the PrP. Differently, no disease-causing changes in the PrP of Nor98-affected sheep have been found in the affected sheep in Sweden. These findings together with observations of a distinct epidemiology, suggest that Nor98 could be the result of a spontaneous conversion of PrPC into PrPSc, similar to that proposed for sporadic Creutzfeldt-Jakob disease and sporadic fatal insomnia.
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    ABSTRACT: Background: transmissible spongiform encephalopathies (prio- nopathies) are neurodegenerative disorders caused by an agent, the prion, which is supposed to consist exclusively of a protein. Objective: to report the Western blot typing results in a series of 25 CJD cases included in the Vigo Brain Bank (BTN-Vigo) in the 2002-2008 period, and to establish a genotype-phenotype correlation. Patients and methods: twenty-five genetically characterized cases have been studied by means of histological, immunohistochemical and Western blot methods applied to representative brain areas, using standardized protocols. Results: based on Western blot protein band patterns and on codon 129 polymorphism, five groups of cases were identified. The so-called classic form of CJD was found in 10 MM1 and three MM2 cases, with no case corresponding to the MM2 sporadic form of fatal insomnia. Cases with valine in codon 129 (both MV2 and VV2) showed the so-called "ataxic variant" phenotype, with a predominance of cerebellar involvement. In one familial CJD case, the most common prion strain in such cases (type 1B) was identified. Conclusions: Western blot analysis allows prion strain identification in all cases and is recommended to study prionopathies. Western blot results, combined with codon 129 polymorphism, show a clear correlation with phenotypic fea- tures of the disease. (Alzheimer. Real Invest Demenc. 2009;42:4-13)
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