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.
"Vacuolation in the hippocampal pyramidal cell layer was observed in the NPDPSC E200K-129M (6 cases out of 7 cases examined) and -129V cases (all 6 cases examined). The thalamic changes noted in our case have been reported only in one case of E200K-129M  and commonly seen in sporadic and familial fatal insomnia [38,39]. "
[Show abstract][Hide abstract] ABSTRACT: A novel point mutation resulting in a glutamate-to-glycine substitution in PRNP at codon 200, E200G with codon 129 MV polymorphism (cis valine) and type 2 PrPSc was identified in a patient with a prolonged disease course leading to pathology-proven Jakob-Creutzfeldt disease. Despite the same codon as the most common genetic form of human PRNP mutation, E200K, this novel mutation (E200G) presented with a different clinical and pathological phenotype, including prolonged duration, large vacuoles, no vacuolation in the hippocampus, severe neuronal loss in the thalamus, mild cerebellar involvement, and abundant punctate linear and curvilinear deposition of PrPSc in synaptic boutons and axonal terminals along the dendrites.
"The Met 129-Asn 178 allele segregates with FFI, while the Val 129-Asn 178 allele segregates with fCJD . Recently, the first cases of a sporadic form of fatal insomnia (sFI) have been reported in a 44-year-old man and a 58-year-old woman [63–65]. FFI and sFI have similar disease phenotypes. "
[Show abstract][Hide abstract] ABSTRACT: Prion diseases are fatal neurodegenerative illnesses, which include Creutzfeldt-Jakob disease in humans and scrapie, chronic wasting disease, and bovine spongiform encephalopathy in animals. They are caused by unconventional infectious agents consisting primarily of misfolded, aggregated, β -sheet-rich isoforms, denoted prions, of the physiological cellular prion protein (PrP(C)). Many lines of evidence suggest that prions (PrP(Sc)) act both as a template for this conversion and as a neurotoxic agent causing neuronal dysfunction and cell death. As such, PrP(Sc) may be considered as both a neuropathological hallmark of the disease and a therapeutic target. Several diagnostic imaging probes have been developed to monitor cerebral amyloid lesions in patients with neurodegenerative disorders (such as Alzheimer's disease, Parkinson's disease, and prion disease). Examples of these probes are Congo red, thioflavin T, and their derivatives. We synthesized a series of styryl derivatives, denoted theranostics, and studied their therapeutic and/or diagnostic potentials. Here we review the salient traits of these small molecules that are able to detect and modulate aggregated forms of several proteins involved in protein misfolding diseases. We then highlight the importance of further studies for their practical implications in therapy and diagnostics.
International Journal of Cell Biology 11/2013; 2013(5012):150952. DOI:10.1155/2013/150952
"The patients showed clinical and neuropathological signs similar to FFI but family history and mutations in PRNP were not evident. All patients were 129 MM homozygotes and biochemical strain typing of these disease subtypes revealed the only difference in the intensity of the unglycosylated fragment of PrPSc type 2; the unglycosylated fragment was under-represented in FFI [25,45,48]. So far, near 24 sFI cases all revealing 129 MM homozygosity and propagating PrPSc type 2 have been reported in various countries of the world . "
[Show abstract][Hide abstract] ABSTRACT: Prion diseases are transmissible, progressive and invariably fatal neurodegenerative conditions associated with misfolding and aggregation of a host-encoded cellular prion protein, PrP(C). They have occurred in a wide range of mammalian species including human. Human prion diseases can arise sporadically, be hereditary or be acquired. Sporadic human prion diseases include Cruetzfeldt-Jacob disease (CJD), fatal insomnia and variably protease-sensitive prionopathy. Genetic or familial prion diseases are caused by autosomal dominantly inherited mutations in the gene encoding for PrP(C) and include familial or genetic CJD, fatal familial insomnia and Gerstmann-Sträussler-Scheinker syndrome. Acquired human prion diseases account for only 5% of cases of human prion disease. They include kuru, iatrogenic CJD and a new variant form of CJD that was transmitted to humans from affected cattle via meat consumption especially brain. This review presents information on the epidemiology, etiology, clinical assessment, neuropathology and public health concerns of human prion diseases. The role of the PrP encoding gene (PRNP) in conferring susceptibility to human prion diseases is also discussed.
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