Prion Protein Type Research Articles

Coexistence of protease sensitive and resistant prion protein in 129VV homozygous sporadic Creutzfeldt–Jakob disease: a case report

IntroductionThe coexistence of different molecular types of classical protease-resistant prion protein in the same individual have been described, however, the simultaneous finding of these with the recently described protease-sensitive variant or variably protease-sensitive prionopathy has, to the best of our knowledge, not yet been reported.Case presentationA 74-year-old Caucasian woman showed a sporadic Creutzfeldt–Jakob disease clinical phenotype with reactive depression, followed by cognitive impairment, akinetic-rigid Parkinsonism with pseudobulbar syndrome and gait impairment with motor apraxia, visuospatial disorientation, and evident frontal dysfunction features such as grasping, palmomental reflex and brisk perioral reflexes. She died at age 77.Neuropathological findings showed: spongiform change in the patient’s cerebral cortex, striatum, thalamus and molecular layer of the cerebellum with proteinase K-sensitive synaptic-like, dot-like or target-like prion protein deposition in the cortex, thalamus and striatum; proteinase K-resistant prion protein in the same regions; and elongated plaque-like proteinase K-resistant prion protein in the molecular layer of the cerebellum. Molecular analysis of prion protein after proteinase K digestion revealed decreased signal intensity in immunoblot, a ladder-like protein pattern, and a 71% reduction of PrPSc signal relative to non-digested material. Her cerebellum showed a 2A prion protein type largely resistant to proteinase K. Genotype of polymorphism at codon 129 was valine homozygous.ConclusionMolecular typing of prion protein along with clinical and neuropathological data revealed, to the best of our knowledge, the first case of the coexistence of different protease-sensitive prion proteins in the same patient in a rare case that did not fulfill the current clinical diagnostic criteria for either probable or possible sporadic Creutzfeldt–Jakob disease. This highlights the importance of molecular analyses of several brain regions in order to correctly diagnose rare and atypical prionopathies.

Infectious titres of sheep scrapie and bovine spongiform encephalopathy agents cannot be accurately predicted from quantitative laboratory test results

It is widely accepted that abnormal forms of the prion protein (PrP) are the best surrogate marker for the infectious agent of prion diseases and, in practice, the detection of such disease-associated (PrP(d)) and/or protease-resistant (PrP(res)) forms of PrP is the cornerstone of diagnosis and surveillance of the transmissible spongiform encephalopathies (TSEs). Nevertheless, some studies question the consistent association between infectivity and abnormal PrP detection. To address this discrepancy, 11 brain samples of sheep affected with natural scrapie or experimental bovine spongiform encephalopathy were selected on the basis of the magnitude and predominant types of PrP(d) accumulation, as shown by immunohistochemical (IHC) examination; contra-lateral hemi-brain samples were inoculated at three different dilutions into transgenic mice overexpressing ovine PrP and were also subjected to quantitative analysis by three biochemical tests (BCTs). Six samples gave 'low' infectious titres (10⁶·⁵ to 10⁶·⁷ LD₅₀ g⁻¹) and five gave 'high titres' (10⁸·¹ to ≥ 10⁸·⁷ LD₅₀ g⁻¹) and, with the exception of the Western blot analysis, those two groups tended to correspond with samples with lower PrP(d)/PrP(res) results by IHC/BCTs. However, no statistical association could be confirmed due to high individual sample variability. It is concluded that although detection of abnormal forms of PrP by laboratory methods remains useful to confirm TSE infection, infectivity titres cannot be predicted from quantitative test results, at least for the TSE sources and host PRNP genotypes used in this study. Furthermore, the near inverse correlation between infectious titres and Western blot results (high protease pre-treatment) argues for a dissociation between infectivity and PrP(res).

Review: Creutzfeldt–Jakob disease: prion protein type, disease phenotype and agent strain

The human transmissible spongiform encephalopathies or human prion diseases are one of the most intensively investigated groups of rare human neurodegenerative conditions. They are generally held to be unique in terms of their complex epidemiology and phenotypic variability, but they may also serve as a paradigm with which other more common protein misfolding disorders might be compared and contrasted. The clinico-pathological phenotype of human prion diseases appears to depend on a complex interaction between the prion protein genotype of the affected individual and the physico-chemical properties of the neurotoxic and transmissible agent, thought to comprise of misfolded prion protein. A major focus of research in recent years has been to define the phenotypic heterogeneity of the recognized human prion diseases, correlate this with molecular-genetic features and then determine whether this molecular-genetic classification of human prion disease defines the biological properties of the agent as determined by animal transmission studies. This review seeks to survey the field as it currently stands, summarize what has been learned, and explore what remains to be investigated in order to obtain a more complete scientific understanding of prion diseases and to protect public health.

The contribution of different prion protein types and host polymorphisms to clinicopathological variations in Creutzfeldt–Jakob disease

Creutzfeldt-Jakob disease is a fatal neurodegenerative disease that primarily affects the central nervous system. In this respect, it can be considered alongside the more frequently occurring neurodegenerative diseases, such as Alzheimer's disease. Creutzfeldt-Jakob disease is perhaps the paradigmatic protein misfolding disorder, so comparisons between the mechanisms involved in Creutzfeldt-Jakob disease and other neurodegenerative diseases associated with protein misfolding (such as the tauopathies and synucleinopathies) may also be informative. Like many of these diseases, Creutzfeldt-Jakob disease occurs sporadically or can, more rarely, be associated with mutations. However, Creutzfeldt-Jakob disease can also be acquired and is experimentally transmissible. These properties have had profound public health implications and made the disease of interest to virologists, in addition to those interested in protein misfolding disorders and neurodegeneration. The possible causes for the pronounced phenotypic variation among different forms of Creutzfeldt-Jakob disease are beginning to become understood, and these appear to depend in large measure on the genetics of the host (specifically the sequence of the prion protein gene, PRNP) and the epigenetic aspects of the agent (thought to be a misfolded and aggregated form of the PRNP gene product, termed a prion). This review will examine whether this model in its present form has sufficient complexity and subtlety to account for the clinicopathological variation evident in Creutzfeldt-Jakob disease and will outline the ways in which a more complete and informative molecular definition of human prions are currently being sought.

Clinical aspects of common genetic Creutzfeldt-Jakob disease

Clinical aspects of common genetic Creutzfeldt-Jakob disease

Co-Occurrence of Types 1 and 2 PrP res in Sporadic Creutzfeldt-Jakob Disease MM1

The genotype (M/M, M/V, or V/V) at polymorphic codon 129 of the human prion protein (PrP) gene and the type (1 or 2) of protease-resistant PrP (PrP(res)) in the brain are major determinants of the clinicopathological phenotypes of sporadic Creutzfeldt-Jakob disease (sCJD). According to this molecular typing system, sCJD has been classified into six subgroups (MM1, MM2, MV1, MV2, VV1, and VV2). Besides these pure subgroups, mixed cases presenting mixed neuropathological phenotypes and more than one PrP(res) type have been found in sCJD. To investigate the frequency of the co-occurrence of types 1 and 2 PrP(res) in sCJD patients classified as MM1, we produced type 2 PrP(res)-specific antibody Tohoku 2 (T2) that can specifically detect the N-terminal cleavage site of type 2 PrP(res) after protease treatment and examined brain samples from 23 patients with sCJD-MM1. Western blot analysis using the T2 antibody revealed that the minority type 2 PrP(res) could be detected in all sCJD-MM1 brain samples including those of the cerebellum where sCJD-MM2 prions rarely accumulate. These results show that the co-occurrence of types 1 and 2 PrP(res) within a single sCJD-MM1 patient is a universal phenomenon. The general co-occurrence of multiple PrP(res) fragments within a single prion strain questions the validity of the conventional molecular typing system.

Cellular prion proteins in human platelets show a phenotype different to those in brain tissues

Prion diseases are characterized by high accumulation of infectious prion proteins (PrP(Sc)) in brains. PrP(Sc) are propagated by the conversion of host-encoded cellular prion proteins (PrP(C)) which are essential for developing the disease but are heterogeneously expressed in brains. The disease can be transmitted to humans and animals through blood and blood products, however, little attention has been given to molecular characterization of PrP(C) in blood cells. In this presented study, we characterized phenotypically PrP(C) of platelets (plt) and characterized the proteins regarding their glycobanding profiles by quantitative immunoblotting using a panel of monoclonal antibodies. The glycosylation patterns of plt and brain PrP(C) were compared using the ratios of di-, mono-, and non-glycosylated prions. The detergent solubility of plt and brain PrP(C) was also analyzed. The distinct banding patterns and detergent solubility of plt PrP(C) differed clearly from the glycosylation profiles and solubility characteristics of brain PrP(C). Plt PrP(C) exhibited single or only few prion protein types, whereas brain PrP(C) showed more extensive banding patterns and lower detergent solubility. Plt PrP(C) are post-translational modified differently from PrP(C) in brain. These findings suggest other or less physiological functions of plt PrP(C) than in brain.

An autopsied case of V180I Creutzfeldt‐Jakob disease presenting with panencephalopathic‐type pathology and a characteristic prion protein type

A 73-year-old Japanese woman showed slowly progressive aphasia, apraxia and dementia. She had no family history of prion disease or dementia. One year later she showed parkinsonism and corticobasal degeneration was initially suspected. On MRI, the left temporal neocortex seemed swollen on T2-weighted images in the initial stage, and a later high-signal intensity region was observed in the cerebral cortex in diffusion-weighted images. The patient developed myoclonus and an akinetic mutism state 15 months and 22 months after onset, respectively. Consecutive electroencephalography revealed no periodic sharp-wave complexes. Prion protein (PrP) gene analysis revealed a valine to isoleucine point mutation at codon 180, and methionine homozygosity at codon 129. This patient's clinical symptoms and disease course were atypical for Creutzfeldt-Jakob disease (CJD), and a stable state with nasal tube-feeding lasted several years. She died of respiratory failure at the age of 81, 102 months after the onset. Autopsy revealed widespread spongiform degeneration with weak synaptic-type PrP deposition, confirming the diagnosis of genetic CJD. Neurons in the cerebral cortex were relatively preserved in number and hypertrophic astrocytosis was generally moderate for such long-term disease, but cerebral white matter showed diffuse severe myelin pallor with tissue rarefaction suggestive of panencephalopatic-type pathology. The cerebellar cortex was relatively well preserved with observation of mild spongiform change in the molecular layer, moderate neuron loss in the Purkinje neuron layer, and scattered small plaque-like PrP deposition. Western blot analysis of protease-resistant PrP showed a characteristic pattern without a diglycoform band. V180I CJD is an interesting form of genetic CJD with regards to the clinicopathologic, molecular and genetic findings.

Codon 129 Polymorphism Specific Cerebrospinal Fluid Proteome Pattern in Sporadic Creutzfeldt−Jakob Disease and the Implication of Glycolytic Enzymes in Prion-Induced Pathology

Cerebrospinal fluid (CSF) contains a dynamic and complex mixture of proteins, which can reflect a physiological and pathological state of the central nervous system. In our present study, we show CSF protein patterns from patients with the two most frequent subtypes of sporadic Creutzfeldt-Jakob disease (sCJD) defined by the codon 129 genotype (MM, MV, and VV) and the protease-resistant form of prion protein (type 1 and type 2). The densitometric analysis of 2D gels showed up-regulation of 27 and down-regulation of 3 proteins in the MM-sCJD as well as the up-regulation of 24 proteins in the VV-sCJD as compared to nondemented control. Almost 40% of sCJD specific regulated proteins in CSF are involved in glucose metabolism, regardless of the codon 129 polymorphism. The increase in CSF levels of lactate dehydrogenase (LDH), glucose-6-phosphate isomerase (G6PI), and fructose-bisphosphate aldolase A (ALDOA) were validated on a larger group of sCJD patients including three possible codon 129 polymorphism carriers and three control groups consisting of nondemented, neurological cases as well as patients suffering from Alzheimer's disease or vascular dementia. Subsequently, the abundance of these glycolytic enzymes in the brain as well as their cellular localization were determined. This study demonstrates for the first time the implication of G6PI in prion-induced pathology as well as its cellular translocalization in sCJD. The identification of sCJD-regulated proteins in CSF of living symptomatic patients in our study can broaden our knowledge about pathological processes occurring in sCJD, as they are still not fully understood.

Creutzfeldt‐Jakob disease with an M232R substitution: report of a patient showing slowly progressive disease with abundant plaque‐like PrP deposits in the cerebellum

Patients with genetic Creutzfeldt-Jakob disease in which arginine is substituted for methionine at codon 232 (M232R) of the prion protein gene (CJD232) have been described in Japan, and a recent study has revealed the presence of two clinical phenotypes: a rapidly progressive type (rapid-type) and a slowly progressive type (slow-type). Although the former is known to show pathologic features similar to those of classical CJD, the neuropathology of the latter still remains unclear. We report the autopsy findings of slow-type CJD232 of 37 months' duration in a 73-year-old man who had methionine homozygosity at codon 129 of the prion protein gene (129MM). His initial symptoms included agraphia and memory disturbance, followed by relatively slowly progressive dementia. Myoclonus and akinetic mutism became evident 5 and 23 months after disease onset, respectively. The electroencephalogram revealed periodic sharp wave complexes at 7 months before death. The neuropathologic features were partly reminiscent of those of MM2-cortical-type sporadic CJD, showing spongiform change of the large confluent vacuole type, neuronal loss with gliosis, and coarse, perivacuolar prion protein deposits, which were later shown to consist of protease-resistant type 2 prion protein, in the cerebral cortex and striatum. It was of considerable interest that not only was the medial thalamus severely involved, but also that the cerebellar cortex showed loss of Purkinje cells and abundant plaque-like prion protein deposits. These findings are not a feature of MM2-cortical-type sporadic CJD. Whether or not the M232R substitution, in combination with the genetic polymorphism and the molecular type of pathological prion protein, really participates in the development of CJD232 and its different phenotypes awaits further studies.

An autopsied case of panencephalopathic‐type Creutzfeldt‐Jakob disease with mutation in the prion protein gene at codon 232 and type 1 prion protein

In this study, we describe the clinicopathologic findings in a 68-year-old man with panencephalopathic-type CJD with a substitution from methionine to arginine at codon 232 (M232R) in the prion protein (PrP) gene and type 1 PrP. Initial symptoms of the patient were a rapidly progressive memory disturbance and disorientation. The patient showed myoclonus and periodic sharp-wave complexes on electroencephalogram in the early stages of disease. Diffusion-weighted MRI along with the presence of both neuron-specific enolase and 14-3-3 protein in the CSF showed similarities to classic-type sporadic CJD. The patient reached the akinetic mutism state 2 months following the onset of symptoms and died after 13 months. Neuropathologic examination revealed panencephalopathic-type CJD pathology including widespread neuron loss with severe hypertrophic astrocytosis and status spongiosus in the cerebral gray matter, particularly in the neocortex. Cerebral white matter and the cerebellum also showed severe involvement. Immunohistochemical staining for PrP showed diffuse gray matter staining, indicating synaptic-type PrP deposition without plaque-type. Two different clinical phenotypes of M232R CJD were recognized despite the presence of the same PrP genotype, and the present case is speculated to correspond to the rapid-type.

Co-existence of scrapie prion protein types 1 and 2 in sporadic Creutzfeldt-Jakob disease: its effect on the phenotype and prion-type characteristics.

Five phenotypically distinct subtypes have been identified in sporadic Creutzfeldt-Jakob disease (sCJD), based on the methionine/valine polymorphic genotype of codon 129 of the prion protein (PrP) gene and the presence of either one of the two protease K-resistant scrapie prion protein (PrP(Sc)) types identified as 1 and 2. The infrequent co-existence of both PrP(Sc) types in the same case has been known for a long time. Recently, it has been reported, using type-specific antibodies, that the PrP(Sc) type 1 is present in all cases of sCJD carrying PrP(Sc) type 2. The consistent co-occurrence of both PrP(Sc) types complicates the diagnosis and the current classification of sCJD, and has implications for the pathogenesis of naturally occurring prion diseases. In the present study, we investigated the prevalence of PrP(Sc) types 1 and 2 co-occurrence, along with its effects on the disease phenotype and PrP(Sc) strain characteristics, comparatively analysing 34 cases of sCJD, all methionine homozygous at codon 129 of the PrP gene (sCJDMM). To minimize overestimating the prevalence of the sCJDMM cases carrying PrP(Sc) types 1 and 2 (sCJDMM1-2), we used proteinase K concentrations designed to hydrolyse all fragments resulting from an incomplete digestion, while preserving the protease-resistant PrP(Sc) core. Furthermore, we used several antibodies to maximize the detection of both PrP(Sc) types. Our data show that sCJDMM cases associated exclusively with either PrP(Sc) type 1 (sCJDMM1) or PrP(Sc) type 2 (sCJDMM2) do exist; we estimate that they account for approximately 56% and 5% of all the sCJDMM cases, respectively; while in 39% of the cases, both PrP(Sc) types 1 and 2 are present together (sCJDMM1-2) either mixed in the same anatomical region or separate in different regions. Clinically, sCJDMM1-2 had an average disease duration intermediate between the other two sCJDMM subtypes. The histopathology was also intermediate, except for the cerebellum where it resembled that of sCJDMM1. These features, along with the PrP immunostaining pattern, offer a diagnostic clue. We also observed a correlation between the disease duration and the prevalence of PrP(Sc) type 2 and sCJDMM2 phenotypes. The use of different antibodies and of the conformational stability immunoassay indicated that the co-existence of types 1 and 2 in the same anatomical region may confer special conformational characteristics to PrP(Sc) types 1 and 2. All of these findings indicate that sCJDMM1-2 should be considered as a separate entity at this time.

An antibody to the aggregated synthetic prion protein peptide (PrP106-126) selectively recognizes disease-associated prion protein (PrP) from human brain specimens.

Human prion diseases are characterized by the conversion of the normal host cellular prion protein (PrP(C)) into an abnormal misfolded form [disease-associated prion protein (PrP(Sc))]. Antibodies that are capable of distinguishing between PrP(C) and PrP(Sc) may prove to be useful, not only for the diagnosis of these diseases, but also for a better understanding of the molecular mechanisms involved in disease pathogenesis. In an attempt to produce such antibodies, we immunized mice with an aggregated peptide spanning amino acid residues 106 to 126 of human PrP (PrP106-126). We were able to isolate and single cell clone a hybridoma cell line (P1:1) which secreted an IgM isotype antibody [monoclonal antibody (mAb P1:1)] that recognized the aggregated, but not the monomeric form of the immunogen. When used in immunoprecipitation assays, the antibody did not recognize normal PrP(C) from non-prion disease brain specimens, but did selectively immunoprecipitate full-length PrP(Sc) from cases of variant and sporadic Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker disease. These results suggest that P1:1 recognizes an epitope formed during the structural rearrangement or aggregation of the PrP that is common to the major PrP(Sc) types found in the most common forms of human prion disease.

Further characterisation of the prion protein molecular types detectable in the NIBSC Creutzfeldt–Jakob disease brain reference materials

Sporadic and variant Creutzfeldt–Jakob disease brain reference materials available from the UK National Institute for Biological Standards and Control have been subjected to further characterisation by Western blot analysis, with particular reference to the co-occurrence of different abnormal disease-associated prion protein (PrP Sc) types. The results confirm the presence of genuine type 1 and type 2 protease-resistant PrP (PrP res) in each of the three sporadic Creutzfeldt–Jakob disease reagents, and provide evidence supporting the lower level presence of type 1 PrP res in the variant Creutzfeldt–Jakob disease reagents. We conclude that these reagents provide a valuable resource for future research and development.

Effects of human PrPSc type and PRNP genotype in an in-vitro conversion assay

Prion protein type and codon 129 genotype are thought to be major determinants of susceptibility and phenotype in human prion diseases. Using an in-vitro system (protein misfolding cyclic amplification) we have attempted to model human prion protein conversion using the abnormal prion protein associated with each of the major sporadic Creutzfeldt-Jakob disease subtypes, in substrates containing the normal cellular form of the prion protein of each of the three possible human PRNP codon 129 polymorphic genotypes. The prion protein type is converted with fidelity in these amplification reactions, but the efficiency of conversion depends both on the methionine/valine polymorphic status of the sporadic Creutzfeldt-Jakob disease seed and substrate homogenate, and on the abnormal prion protein type.

Plaque-type deposition of prion protein in the damaged white matter of sporadic Creutzfeldt-Jakob disease MM1 patients

Plaque-type deposition of prion protein (PrP) in the brain has been extremely rare in sporadic Creutzfeldt-Jakob disease patients with methionine homozygosity at polymorphic codon 129 of the PrP gene and type 1 abnormal isoform of PrP (sCJD-MM1). Here we report three sCJD-MM1 patients who showed prominent PrP-positive amyloid plaques in the cerebral and cerebellar white matter. All three patients showed clinical courses of long duration (2 years < or =), particularly at the end-stage. The white matter of these patients was severely damaged because of the prolonged disease duration. Furthermore, Alzheimer's amyloid precursor protein, which accumulates within the axonal swellings under pathological conditions, co-accumulated with the PrP-amyloid plaques. These findings suggest that the axonal damage reflecting the prolonged disease duration causes the deposition of PrP-amyloid plaques in the white matter. The present study shows that PrP-amyloid plaques can occur in the white matter of sCJD-MM1 cases.

Pruritus is a common feature in sheep infected with the BSE agent

BackgroundThe variability in the clinical or pathological presentation of transmissible spongiform encephalopathies (TSEs) in sheep, such as scrapie and bovine spongiform encephalopathy (BSE), has been attributed to prion protein genotype, strain, breed, clinical duration, dose, route and type of inoculum and the age at infection. The study aimed to describe the clinical signs in sheep infected with the BSE agent throughout its clinical course to determine whether the clinical signs were as variable as described for classical scrapie in sheep. The clinical signs were compared to BSE-negative sheep to assess if disease-specific clinical markers exist.ResultsForty-seven (34%) of 139 sheep, which comprised 123 challenged sheep and 16 undosed controls, were positive for BSE. Affected sheep belonged to five different breeds and three different genotypes (ARQ/ARQ, VRQ/VRQ and AHQ/AHQ). None of the controls or BSE exposed sheep with ARR alleles were positive. Pruritus was present in 41 (87%) BSE positive sheep; the remaining six were judged to be pre-clinically infected. Testing of the response to scratching along the dorsum of a sheep proved to be a good indicator of clinical disease with a test sensitivity of 85% and specificity of 98% and usually coincided with weight loss. Clinical signs that were displayed significantly earlier in BSE positive cases compared to negative cases were behavioural changes, pruritic behaviour, a positive scratch test, alopecia, skin lesions, teeth grinding, tremor, ataxia, loss of weight and loss of body condition. The frequency and severity of each specific clinical sign usually increased with the progression of disease over a period of 16–20 weeks.ConclusionOur results suggest that BSE in sheep presents with relatively uniform clinical signs, with pruritus of increased severity and abnormalities in behaviour or movement as the disease progressed. Based on the studied sheep, these clinical features appear to be independent of breed, affected genotype, dose, route of inoculation and whether BSE was passed into sheep from cattle or from other sheep, suggesting that the clinical phenotype of BSE is influenced by the TSE strain more than by other factors. The clinical phenotype of BSE in the genotypes and breed studied was indistinguishable from that described for classical scrapie cases.

Strain‐Associated Variations in Abnormal PrP Trafficking of Sheep Scrapie

Prion diseases are associated with the accumulation of an abnormal form of the host‐coded prion protein (PrP). It is postulated that different tertiary or quaternary structures of infectious PrP provide the information necessary to code for strain properties. We show here that different light microscopic types of abnormal PrP (PrPd) accumulation found in each of 10 sheep scrapie cases correspond ultrastructurally with abnormal endocytosis, increased endo‐lysosomes, microfolding of plasma membranes, extracellular PrPd release and intercellular PrPd transfer of neurons and/or glia. The same accumulation patterns of PrPd and associated subcellular lesions were present in each of two scrapie strains present, but they were present in different proportions. The observations suggest that different trafficking pathways of PrPd are influenced by strain and cell type and that a single prion strain causes several PrPd–protein interactions at the cell membrane. These results imply that strains may contain or result in production of multiple isoforms of PrPd.

SPORADIC FATAL INSOMNIA IN A FATAL FAMILIAL INSOMNIA PEDIGREE

Transmissible spongiform encephalopathies (TSEs) or prion diseases are a group of neurodegenerative disorders which uniquely comprise sporadic, genetic, and acquired forms.1 According to the leading theory, genetic TSEs are caused by mutations in the prion protein gene ( PRNP ), the acquired forms derive from an exogenous prion infection, while the sporadic forms arise spontaneously, as a consequence of a somatic mutation or a stochastic metabolic event. At least six phenotypic subtypes of sporadic human TSEs exist, which has been shown to correlate with both the genotype at polymorphic PRNP codon 129 and either one of two types of abnormal prion protein (PrPSc) with distinct physicochemical properties.2 The phenotypic variability of genetic TSEs broadly reproduces that of the sporadic form, although the relative incidence of each subtype varies considerably in the two forms. The fatal insomnia (FI) phenotype, for example, is the third most frequent genetic prion disease but the rarest of the sporadic TSE subtypes, with only 15 cases diagnosed worldwide.1,3 Given their rarity and supposedly distinct etiology, the occurrence of distinct TSE forms among genetically related individuals is not expected. Here we describe the co-occurrence of both sporadic and genetic forms of FI within …

Creutzfeldt-Jakob Disease, Prion Protein Gene Codon 129VV, and a Novel PrPSc Type in a Young British Woman

Variant Creutzfeldt-Jakob disease (vCJD) is an acquired prion disease causally related to bovine spongiform encephalopathy that has occurred predominantly in young adults. All clinical cases studied have been methionine homozygotes at codon 129 of the prion protein gene (PRNP) with distinctive neuropathological findings and molecular strain type (PrP(Sc) type 4). Modeling studies in transgenic mice suggest that other PRNP genotypes will also be susceptible to infection with bovine spongiform encephalopathy prions but may develop distinctive phenotypes. To describe the histopathologic and molecular investigation in a young British woman with atypical sporadic CJD and valine homozygosity at PRNP codon 129. Case report, autopsy, and molecular analysis. Specialist neurology referral center, together with the laboratory services of the MRC [Medical Research Council] Prion Unit. Subject Single hospitalized patient. Autopsy findings and molecular investigation results. Autopsy findings were atypical of sporadic CJD, with marked gray and white matter degeneration and widespread prion protein (PrP) deposition. Lymphoreticular tissue was not available for analysis. Molecular analysis of PrP(Sc) (the scrapie isoform of PrP) from cerebellar tissue demonstrated a novel PrP(Sc) type similar to that seen in vCJD (PrP(Sc) type 4). However, this could be distinguished from the typical vCJD pattern by an altered protease cleavage site in the presence of the metal ion chelator EDTA. Further studies will be required to characterize the prion strain seen in this patient and to investigate its etiologic relationship with bovine spongiform encephalopathy. This case illustrates the importance of molecular analysis of prion disease, including the use of EDTA to investigate the metal dependence of protease cleavage patterns of PrP(Sc).