Cases Of Prion Disease Research Articles

Search for a genetic cause of variably protease-sensitive prionopathy.

Prion disease is caused by misfolding of the prion protein (PrP), and can be either sporadic genetic, or acquired. Acquired cases arising from infection through dietary or medical routes are exceedingly rare today (<1% of cases). Sporadic cases occur apparently at random, without any major genetic risk factors, and are not passed down to subsequent generations. All cases of genetic prion disease to date have been traced to DNA changes that alter the amino acid sequence of PrP, and children of people with genetic prion disease are at 50/50 risk of inheriting these autosomal dominant DNA changes. Variably protease sensitive prionopathy, or VPSPr, is a rare and unusual subtype of prion disease, in which there are no changes in PrP's amino acid sequence, and yet, a high proportion of patients appear to have a family history of dementia, although none to date have had family members diagnosed with prion disease specifically. VPSPr is currently categorized as a sporadic prion disease, but it has been speculated that it may have a genetic cause in a different gene or in a region of the PrP gene that does not change the amino acid sequence. Here we performed DNA sequencing on 67 VPSPr cases to search for a genetic cause. We found no DNA changes that could potentially cause VPSPr. While it is difficult to prove the negative - a causal genetic change could still exist in some part of the genome where we did not search - our data support the notion that VPSPr is truly sporadic in nature, and that risk of VPSPr is not transmitted in families.

Atypical Case of Prion Disease with D178N-homozygous 129M Genotype

Atypical Case of Prion Disease with D178N-homozygous 129M Genotype

Convergent generation of atypical prions in knockin mouse models of genetic prion disease.

Most cases of human prion disease arise due to spontaneous misfolding of WT or mutant prion protein, yet recapitulating this event in animal models has proven challenging. It remains unclear whether spontaneous prion generation can occur within the mouse lifespan in the absence of protein overexpression and how disease-causing mutations affect prion strain properties. To address these issues, we generated knockin mice that express the misfolding-prone bank vole prion protein (BVPrP). While mice expressing WT BVPrP (I109 variant) remained free from neurological disease, a subset of mice expressing BVPrP with mutations (D178N or E200K) causing genetic prion disease developed progressive neurological illness. Brains from spontaneously ill knockin mice contained prion disease-specific neuropathological changes as well as atypical protease-resistant BVPrP. Moreover, brain extracts from spontaneously ill D178N- or E200K-mutant BVPrP-knockin mice exhibited prion seeding activity and transmitted disease to mice expressing WT BVPrP. Surprisingly, the properties of the D178N- and E200K-mutant prions appeared identical before and after transmission, suggesting that both mutations guide the formation of a similar atypical prion strain. These findings imply that knockin mice expressing mutant BVPrP spontaneously develop a bona fide prion disease and that mutations causing prion diseases may share a uniform initial mechanism of action.

Neuropathologically directed profiling of PRNP somatic and germline variants in sporadic human prion disease.

Creutzfeldt-Jakob Disease (CJD), the most common human prion disease, is associated with pathologic misfolding of the prion protein (PrP), encoded by the PRNP gene. Of human prion disease cases,<1% were transmitted by misfolded PrP, ~ 15% are inherited, and ~ 85% are sporadic (sCJD). While familial cases are inherited through germline mutations in PRNP, the cause of sCJD is unknown. Somatic mutations have been hypothesized as a cause of sCJD, and recent studies have revealed that somatic mutations accumulate in neurons during aging. To investigate the hypothesis that somatic mutations in PRNP may underlie sCJD, we performed deep DNA sequencing of PRNP in 205 sCJD cases and 170 age-matched non-disease controls. We included 5 cases of Heidenhain variant sporadic CJD (H-sCJD), where visual symptomatology and neuropathology implicate localized initiation of prion formation, and examined multiple regions across the brain including in the affected occipital cortex. We employed Multiple Independent Primer PCR Sequencing (MIPP-Seq) with a median depth of > 5000× across the PRNP coding region and analyzed for variants using MosaicHunter. An allele mixing experiment showed positive detection of variants in bulk DNA at a variant allele fraction (VAF) as low as 0.2%. We observed multiple polymorphic germline variants among individuals in our cohort. However, we did not identify bona fide somatic variants in sCJD, including across multiple affected regions in H-sCJD, nor in control individuals. Beyond our stringent variant-identification pipeline, we also analyzed VAFs from raw sequencing data, and observed no evidence of prion disease enrichment for the known germline pathogenic variants P102L, D178N, and E200K. The lack of PRNP pathogenic somatic mutations in H-sCJD or the broader cohort of sCJD suggests that clonal somatic mutations may not play a major role in sporadic prion disease. With H-sCJD representing a localized presentation of neurodegeneration, this serves as a test of the potential role of clonal somatic mutations in genes known to cause familial neurodegeneration.

Neuropathologically-directed profiling of PRNP somatic and germline variants in sporadic human prion disease.

Creutzfeldt-Jakob Disease (CJD), the most common human prion disease, is associated with pathologic misfolding of the prion protein (PrP), encoded by the PRNP gene. Of human prion disease cases, ~1% were transmitted by misfolded PrP, ~15% are inherited, and ~85% are sporadic (sCJD). While familial cases are inherited through germline mutations in PRNP, the cause of sCJD is unknown. Somatic mutations have been hypothesized as a cause of sCJD, and recent studies have revealed that somatic mutations accumulate in neurons during aging. To investigate the hypothesis that somatic mutations in PRNP may underlie sCJD, we performed deep DNA sequencing of PRNP in 205 sCJD cases and 170 age-matched non-disease controls. We included 5 cases of Heidenhain variant sporadic CJD (H-sCJD), where visual symptomatology and neuropathology implicate focal initiation of prion formation, and examined multiple regions across the brain including in the affected occipital cortex. We employed Multiple Independent Primer PCR Sequencing (MIPP-Seq) with a median depth of >5,000X across the PRNP coding region and analyzed for variants using MosaicHunter. An allele mixing experiment showed positive detection of variants in bulk DNA at a variant allele fraction (VAF) as low as 0.2%. We observed multiple polymorphic germline variants among individuals in our cohort. However, we did not identify bona fide somatic variants in sCJD, including across multiple affected regions in H-sCJD, nor in control individuals. Beyond our stringent variant-identification pipeline, we also analyzed VAFs from raw sequencing data, and observed no evidence of prion disease enrichment for the known germline pathogenic variants P102L, D178N, and E200K. The lack of PRNP pathogenic somatic mutations in H-sCJD or the broader cohort of sCJD suggests that clonal somatic mutations may not play a major role in sporadic prion disease. With H-sCJD representing a focal presentation of neurodegeneration, this serves as a test of the potential role of clonal somatic mutations in genes known to cause familial neurodegeneration.

The first report of single nucleotide polymorphisms in the open reading frame of the prion-like protein gene in rabbits.

Natural cases of prion disease have not been reported in rabbits, and prior attempts to identify a prion conversion agent have been unsuccessful. However, recent applications of prion seed amplifying experimental techniques have sparked renewed interest in the potential susceptibility of rabbits to prion disease infections. Among several factors related to prion disease, polymorphisms within the prion-like protein gene (PRND), a member of the prion protein family, have been reported as significantly associated with disease susceptibility in various species. Therefore, our study aimed to investigate polymorphisms in the PRND gene of rabbits and analyze their genetic characteristics. Genomic DNA was extracted from 207 rabbit samples to investigate leporine PRND polymorphisms. Subsequently, amplicon sequencing targeting the coding region of the leporine PRND gene was conducted. Additionally, linkage disequilibrium (LD) analysis was employed to assess the connection within and between loci. The impact of non-synonymous single nucleotide polymorphisms (SNPs) on the Doppel protein was evaluated using PolyPhen-2. We found nine novel SNPs in the leporine PRND gene: c.18A > G, c.76G > C, c.128C > T, c.146C > T, c.315A > G, c.488G > A, c.525G > C, c.544G > A, and c.579A > G. Notably, seven of these PRND SNPs, excluding c.525G > C and c.579A > G, exhibited strong LD values exceeding 0.3. In addition, LD analysis confirmed a robust link between PRNP SNP c.234C > T and PRND SNPs at c.525G > C and c.579A > G. Furthermore, according to PolyPhen-2 and SIFT analyses, the four non-synonymous SNPs were predicted to have deleterious effects on the function or structure of the Doppel protein. However, PANTHER and Missense3D did not indicate such effects. In this paper, we have identified novel SNPs in the rabbit PRND gene and predicted their potential detrimental effects on protein function or structure through four non-synonymous SNPs. Additionally, we observed a genetic linkage between SNPs in the PRND and PRNP genes. These findings may provide insights into understanding the characteristics of rabbits as partially resistant species. To the best of our knowledge, this study is the first to genetically characterize PRND SNPs in rabbits.

Sleep disturbance in clinical and preclinical scrapie-infected sheep measured by polysomnography

Neurodegenerative diseases are characterised by neuronal loss and abnormal deposition of pathological proteins in the nervous system. Among the most common neurodegenerative diseases are Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease and transmissible spongiform encephalopathies (TSEs). Sleep and circadian rhythm disturbances are one of the most common symptoms in patients with neurodegenerative diseases. Currently, one of the main objectives in the study of TSEs is to try to establish an early diagnosis, as clinical signs do not appear until the damage to the central nervous system is very advanced, which prevents any therapeutic approach. In this paper, we provide the first description of sleep disturbance caused by classical scrapie in clinical and preclinical sheep using polysomnography compared to healthy controls. Fifteen sheep classified into three groups, clinical, preclinical and negative control, were analysed. The results show a decrease in total sleep time as the disease progresses, with significant changes between control, clinical and pre-clinical animals. The results also show an increase in sleep fragmentation in clinical animals compared to preclinical and control animals. In addition, sheep with clinical scrapie show a total loss of Rapid Eye Movement sleep (REM) and alterations in Non Rapid Eyes Movement sleep (NREM) compared to control sheep, demonstrating more shallow sleep. Although further research is needed, these results suggest that prion diseases also produce sleep disturbances in animals and that polysomnography could be a diagnostic tool of interest in clinical and preclinical cases of prion diseases.

Absence of evidence of transfusion transmission risk of Creutzfeldt-Jakob disease in the United States: Results froma 28-year lookback study.

For many years, there has been concern about the risk of transmission of classic forms of Creutzfeldt-Jakob disease (CJD) by blood transfusion, particularly after the recognition of such transmission of variant CJD (vCJD). We report on a 28-year lookback study of recipients of blood from donors who subsequently developed CJD. Patients with diagnosed CJD and a history of blood donation were identified. Blood centers were asked to provide information about the distribution of the donations and consignees were requested to provide information about the recipients of the donations. Vital status of each available recipient was determined and, if deceased, the reported cause(s) of death were obtained primarily from the National Death Index. All recipients included in the study database contributed person-time up to the last recorded review of vital status. There were 84 eligible donors who gave 3284 transfusable components, and it was possible to evaluate 1245 recipients, totaling 6495 person-years of observation. The mean observation period per recipient was 5.5 years with a maximum of 51 years. No case of CJD or prion disease was reported among the recipient population. The study suggests that CJD may not be transfusion-transmissible, a position in agreement with similar findings from two similar European reports amounting to an overall observation period of 15,500 person-years. These studies have supported the conclusion that the risk, if any, of transmission of CJD by blood products is extremely small and remains theoretical.

The first report of polymorphisms of the prion protein gene (PRNP) in Pekin ducks (Anas platyrhynchos domestica).

Prion diseases have been extensively reported in various mammalian species and are caused by a pathogenic prion protein (PrPSc), which is a misfolded version of cellular prion protein (PrPC). Notably, no cases of prion disease have been reported in birds. Single nucleotide polymorphisms (SNPs) of the prion protein gene (PRNP) that encodes PrP have been associated with susceptibility to prion diseases in several species. However, no studies on PRNP polymorphisms in domestic ducks have been reported thus far. To investigate PRNP polymorphisms in domestic ducks, we isolated genomic DNA from 214 Pekin duck samples and sequenced the coding region of the Pekin duck PRNP gene. We analyzed genotype, allele, and haplotype distributions and linkage disequilibrium (LD) among the SNPs of the Pekin duck PRNP gene. In addition, we evaluated the effects of the one non-synonymous SNP on the function and structure of PrP using the PROVEAN, PANTHER, SNPs & GO, SODA, and AMYCO in silico prediction programs. We found five novel SNPs, c.441 T > C, c.495 T > C, c.582A > G, c.710C > T(P237L), and c.729C > T, in the ORF region of the PRNP gene in 214 Pekin duck samples. We observed strong LD between c.441 T > C and c.582A > G (0.479), and interestingly, the link between c.495 T > C and c.729C > T was in perfect LD, with an r2 value of 1.0. In addition, we identified the five major haplotype frequencies: TTACC, CTGCC, CTACC, CCGCT, and CTATC. Furthermore, we found that the non-synonymous SNP, c.710C > T (P237L), had no detrimental effects on the function or structure of Pekin duck PrP. However, the non-synonymous SNP had deleterious effects on the aggregation propensity and solubility of Pekin duck PrP compared with wildtype Pekin duck PrP. To the best of our knowledge, this study is the first report on the genetic characteristics of PRNP SNPs in Pekin ducks.

Enhanced Creutzfeldt-Jakob disease surveillance in the older population: Assessment of a protocol for screening brain tissue donations for prion disease.

Human prion diseases, including Creutzfeldt-Jakob disease (CJD), occur in sporadic, genetic, and acquired forms. Variant Creutzfeldt-Jakob disease (vCJD) first reported in 1996 in the United Kingdom (UK), resulted from contamination of food with bovine spongiform encephalopathy. There is a concern that UK national surveillance mechanisms might miss some CJD cases (including vCJD), particularly in the older population where other neurodegenerative disorders are more prevalent. We developed a highly sensitive protocol for analysing autopsy brain tissue for the misfolded prion protein (PrPSc ) associated with prion disease, which could be used to screen for prion disease in the elderly. Brain tissue samples from 331 donors to the Edinburgh Brain and Tissue Bank (EBTB), from 2005 to 2022, were analysed, using immunohistochemical analysis on fixed tissue, and five biochemical tests on frozen specimens from six brain regions, based on different principles for detecting PrPSc . An algorithm was established for classifying the biochemical results. To test the effectiveness of the protocol, several neuropathologically confirmed prion disease controls, including vCJD, were included and blinded in the study cohort. On unblinding, all the positive control cases had been correctly identified. No other cases tested positive; our analysis uncovered no overlooked prion disease cases. Our algorithm for classifying cases was effective for handling anomalous biochemical results. An overall analysis suggested that a reduced biochemical protocol employing only three of the five tests on only two brain tissue regions gave sufficient sensitivity and specificity. We conclude that this protocol may be useful as a UK-wide screening programme for human prion disease in selected brains from autopsies in the elderly. Further improvements to the protocol were suggested by enhancements of the in vitro conversion assays made during the course of this study.

The Zoonotic Potential of Chronic Wasting Disease—A Review

Prion diseases are transmissible neurodegenerative disorders that affect humans and ruminant species consumed by humans. Ruminant prion diseases include bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep and goats and chronic wasting disease (CWD) in cervids. In 1996, prions causing BSE were identified as the cause of a new prion disease in humans; variant Creutzfeldt-Jakob disease (vCJD). This sparked a food safety crisis and unprecedented protective measures to reduce human exposure to livestock prions. CWD continues to spread in North America, and now affects free-ranging and/or farmed cervids in 30 US states and four Canadian provinces. The recent discovery in Europe of previously unrecognized CWD strains has further heightened concerns about CWD as a food pathogen. The escalating CWD prevalence in enzootic areas and its appearance in a new species (reindeer) and new geographical locations, increase human exposure and the risk of CWD strain adaptation to humans. No cases of human prion disease caused by CWD have been recorded, and most experimental data suggest that the zoonotic risk of CWD is very low. However, the understanding of these diseases is still incomplete (e.g., origin, transmission properties and ecology), suggesting that precautionary measures should be implemented to minimize human exposure.

Emergence of a New Creutzfeldt-Jakob Disease: 26 Cases of the Human Version of Mad-Cow Disease, Days After a COVID-19 Injection

Creutzfeldt-Jakob Disease, the formerly rare but universally fatal prion disease in humans, normally progresses over several decades before it leads to death. In the Appendix to this paper, we highlight the presence of a prion region in the spike protein of the original SARS-CoV-2, and in all the “vaccine” variants built from the Wuhan virus. The prion region in the spike of SARS-CoV-2 has a density of mutations eight times greater than that of the rest of the spike, and, yet, strangely that entire prion region disappears completely in the Omicron variant. In the main body of our text, we present 26 cases of Creuzfeldt-Jacob Disease, all diagnosed in 2021 with the first symptoms appearing within an average of 11.38 days after a Pfizer, Moderna, or AstraZeneca COVID-19 injection. Because the causal progression, the etiopathogenesis, of these atypical and new cases of human prion disease — cases of what is apparently a totally new form of rapidly developing Creuzfeldt-Jacob Disease — we focus on the chronology of the symptomatic development. We consider it from an anamnestic point of view — one in which we compare the typical development of pre-COVID cases of Creuzfeldt-Jacob Disease to the extremely accelerated development of similar symptoms in the 26 cases under examination. By such an approach, we hope to work out the etiopathogenesis critical to understanding this new and much more rapidly developing human prion disease. By recalling the sequential pathway of that the formerly subacute and slowly developing disease followed in the past, and by comparing it with this new, extremely acute, rapidly developing prion disease — one following closely after one or more of the COVID-19 injections — we believe it is correct to infer that the injections caused the disease in these 26 cases. If so, they have probably also caused a many other cases that have gone undiagnosed because of their rapid progression to death. By late 2021, 20 had died within 4.76 months of the offending injection. Of those, 8 died suddenly within 2.5 months confirming the rapid progression of this accelerated form of Creuzfeldt-Jacob Disease. By June 2022, 5 more patients had died, and at the time of this current writing, only 1 remains still alive.

Gerstmann–Sträussler–Scheinker syndrome with early-onset spinocerebellar ataxia phenotype

The article presents a description of the family case of rare hereditary prion disease – Gerstmann–Sträussler–Scheinker syndrome with a verified p.P102L mutation in the PRNP gene. The clinical picture was represented by progressive cerebellar ataxia, pyramidal signs, bulbar syndrome, and neuropathy, which made it possible to establish a preliminary diagnosis of autosomal dominant spinocerebellar ataxia. Subsequently, the final diagnosis was verified using the massive parallel sequencing technology. The features of this observation are the variable age of onset within the family, with the unusually early age of the disease onset in the proband (age of 25 years), the absence of cognitive impairment, as well as the absence of pathological changes in the electroencephalography and brain MRI study. The possible modifying role of polymorphism in codon 129 of the PRNP gene (129Val) in the disease phenotype formation, as well as the clinical findings and diagnostic methods of this syndrome are discussed.

Creutzfeldt-Jakob Disease and Lyodura:A Special Reference to Prion Disease Control in the Field of Neurosurgery

In Japan, 156 cases of dura mater-transplanted Creutzfeldt-Jakob disease(dCJD)with a history of Lyodura transplantation have been confirmed until February 2022, with only a few new cases still being identified. The history of Lyodura transplantation is one involving a neurosurgical procedure. The cumulative global number of cases of bovine spongiform encephalopathy-related variant CJD(BSE-related vCJD), which has shaken societies around the world, is 232 as of 2019. Thus, the impact of dCJD on the society in Japan needs no explanation. Thanks to the world's concerted efforts in research and countermeasures, medically induced prion diseases are finally becoming a thing of the past. However, due to the extremely long incubation period of CJD and the difficulty of tracing the source of infection, immediate action in the event of an outbreak is not possible, and efforts must focus on preventing disease outbreaks. Independent of this, approximately 200 cases of solitary and hereditary prion diseases occur annually in Japan. If neurosurgery must be performed on such patients, secondary transmission of prion disease by neurosurgical instruments must be prevented. Therefore, sterilization methods for neurosurgical instruments are critical, and various measures including sterilization methods have been determined and published by a research group designated by the Japanese Ministry of Health, Labour and Welfare. The sterilization of neurosurgical instruments should comply with the latest guidelines that are published by this study group.

Characteristics of Different Types of Prion Diseases - China's Surveillance.

This report briefly described the establishment and implementation of national surveillance for human prion disease (PrD) in China. Reported cases came from Chinese surveillance network for PrD. Immunohistochemistry, Western blot, enzyme-linked immunosorbent assay (ELISA), Polymerase Chain Reaction (PCR), and real-time quaking-induced conversion (RT-QuIC) tests were used for the samples of brain, cerebrospinal fluid (CSF), and blood. Diagnosis standard for the PrDs is based on the National Commission of Health (WS/T 562-2017). The study summarized major epidemiological, clinical and laboratory features of more than 2,100 diagnosed different types of Chinese PrD cases. Sporadic Creutzfeldt-Jacob disease (sCJD) is the predominant type of PrD (88.7%). 19 different genotypes of genetic PrDs (gPrDs) were identified, accounting for about 11.3% of all PrDs, revealing ethno-relationships. No iatrogenic CJD (iCJD) and variant CJD (vCJD) was identified. The characteristics of different types of sCJD in China showed similar features as those reported globally, but gPrDs showed an obvious ethno-relationship.

A clinicopathological study of selected cognitive impairment cases in Lothian, Scotland: enhanced CJD surveillance in the 65 + population group

BackgroundVariant Creutzfeldt-Jakob Disease (vCJD) is primarily associated with dietary exposure to bovine-spongiform-encephalopathy. Cases may be missed in the elderly population where dementia is common with less frequent referral to specialist neurological services. This study’s twin aims were to determine the feasibility of a method to detect possible missed cases in the elderly population and to identify any such cases.MethodsA multi-site study was set-up in Lothian in 2016, to determine the feasibility of enhanced CJD-surveillance in the 65 + population-group, and undertake a clinicopathological investigation of patients with features of ‘atypical’ dementia.ResultsThirty patients are included; 63% male, 37% female. They were referred because of at least one neurological feature regarded as ‘atypical’ (for the common dementing illnesses): cerebellar ataxia, rapid progression, or somato-sensory features. Mean-age at symptom-onset (66 years, range 53–82 years), the time between onset-of-symptoms and referral to the study (7 years, range 1–13 years), and duration-of-illness from onset-of-symptoms until death or the censor-date (9.5 years, range 1.1–17.4 years) were determined. By the censor-date, 9 cases were alive and 21 had died. Neuropathological investigations were performed on 10 cases, confirming: Alzheimer’s disease only (2 cases), mixed Alzheimer’s disease with Lewy bodies (2 cases), mixed Alzheimer’s disease with amyloid angiopathy (1 case), moderate non-amyloid small vessel angiopathy (1 case), a non-specific neurodegenerative disorder (1 case), Parkinson's disease with Lewy body dementia (1 case), and Lewy body dementia (2 cases). No prion disease cases of any type were detected.ConclusionThe surveillance approach used was well received by the local clinicians and patients, though there were challenges in recruiting sufficient cases; far fewer than expected were identified, referred, and recruited. Further research is required to determine how such difficulties might be overcome. No missed cases of vCJD were found. However, there remains uncertainty whether this is because missed cases are very uncommon or because the study had insufficient power to detect them.

Genetic prion diseases presenting as frontotemporal dementia: clinical features and diagnostic challenge

BackgroundTo elucidate the clinical and ancillary features of genetic prion diseases (gPrDs) presenting with frontotemporal dementia (FTD) to aid early identification.MethodsGlobal data of gPrDs presenting with FTD caused by prion protein gene mutations were collected from literature review and our records. Fifty-one cases of typical FTD and 136 cases of prion diseases admitted to our institution were included as controls. Clinical and ancillary data of the different groups were compared.ResultsForty-nine cases of gPrDs presenting with FTD were identified. Compared to FTD or prion diseases, gPrDs presenting with FTD were characterized by earlier onset age (median 45 vs. 61/60 years, P < 0.001, P < 0.001) and higher incidence of positive family history (81.6% vs. 27.5/13.2%, P < 0.001, P < 0.001). Furthermore, GPrDs presenting with FTD exhibited shorter duration (median 5 vs. 8 years) and a higher rate of parkinsonism (63.7% vs. 9.8%, P < 0.001), pyramidal signs (39.1% vs. 7.8%, P = 0.001), mutism (35.9% vs. 0%, P < 0.001), seizures (25.8% vs. 0%, P < 0.001), myoclonus (22.5% vs. 0%, P < 0.001), and hyperintensity on MRI (25.0% vs. 0, P < 0.001) compared to FTD. Compared to prion diseases, gPrDs presenting with FTD had a longer duration of symptoms (median 5 vs. 1.1 years, P < 0.001), higher rates of frontotemporal atrophy (89.7% vs. 3.3%, P < 0.001), lower rates of periodic short-wave complexes on EEG (0% vs. 30.3%, P = 0.001), and hyperintensity on MRI (25.0% vs. 83.0%, P < 0.001). The frequency of codon 129 Val allele in gPrDs presenting with FTD was significantly higher than that reported in the literature for gPrDs in the Caucasian and East Asian populations (33.3% vs. 19.2%/8.0%, P = 0.005, P < 0.001).ConclusionsGPrDs presenting with FTD are characterized by early-onset, high incidence of positive family history, high frequency of the Val allele at codon 129, overlapping symptoms with prion disease and FTD, and ancillary features closer to FTD. PRNP mutations may be a rare cause in the FTD spectrum, and PRNP genotyping should be considered in patients with these features.

Diagnostic accuracy of cerebrospinal fluid biomarkers in genetic prion diseases.

Genetic prion diseases are a rare and diverse group of fatal neurodegenerative disorders caused by pathogenic sequence variations in the prion protein gene, PRNP. Data on CSF biomarkers in patients with genetic prion diseases are limited and conflicting results have been reported for unclear reasons.Here, we aimed to analyse the diagnostic accuracy of CSF biomarkers currently used in prion clinical diagnosis in 302 symptomatic genetic prion disease cases from 11 prion diagnostic centres, encompassing a total of 36 different pathogenic sequence variations within the open reading frame of PRNP.CSF samples were assessed for the surrogate markers of neurodegeneration, 14-3-3 protein (14-3-3), total-tau protein (t-tau) and α-synuclein and for prion seeding activity through the real-time quaking-induced conversion assay. Biomarker results were compared with those obtained in healthy and neurological controls. For the most prevalent PRNP pathogenic sequence variations, biomarker accuracy and associations between biomarkers, demographic and genetic determinants were assessed. Additionally, the prognostic value of biomarkers for predicting total disease duration from symptom onset to death was investigated.High sensitivity of the four biomarkers was detected for genetic Creutzfeldt–Jakob disease associated with the E200K and V210I mutations, but low sensitivity was observed for mutations associated with Gerstmann–Sträussler–Scheinker syndrome and fatal familial insomnia. All biomarkers showed good to excellent specificity using the standard cut-offs often used for sporadic Creutzfeldt–Jakob disease. In genetic prion diseases related to octapeptide repeat insertions, the biomarker sensitivity correlated with the number of repeats. New genetic prion disease-specific cut-offs for 14-3-3, t-tau and α-synuclein were calculated. Disease duration in genetic Creutzfeldt–Jakob disease-E200K, Gerstmann–Sträussler–Scheinker-P102L and fatal familial insomnia was highly dependent on PRNP codon 129 MV polymorphism and was significantly associated with biomarker levels.In a large cohort of genetic prion diseases, the simultaneous analysis of CSF prion disease biomarkers allowed the determination of new mutation-specific cut-offs improving the discrimination of genetic prion disease cases and unveiled genetic prion disease-specific associations with disease duration.

New prion protein mutation (T183S) with atypical parkinsonism and GSS-like neuropathology

The Canadian CJD surveillance, active since 1998, has reported 1133 prion disease cases. The mortality rate of CJD in Canada averaged 1.96/1,000,000 over the past 5 years. 7% of the cases were genetic in origin.

Characterization of Prion Disease Associated with a Two-Octapeptide Repeat Insertion.

Genetic prion disease accounts for 10–15% of prion disease. While insertion of four or more octapeptide repeats are clearly pathogenic, smaller repeat insertions have an unclear pathogenicity. The goal of this case series was to provide an insight into the characteristics of the 2-octapeptide repeat genetic variant and to provide insight into the risk for Creutzfeldt–Jakob disease in asymptomatic carriers. 2-octapeptide repeat insertion prion disease cases were collected from the National Prion Disease Pathology Surveillance Center (US), the National Prion Clinic (UK), and the National Creutzfeldt–Jakob Disease Registry (Australia). Three largescale population genetic databases were queried for the 2-octapeptide repeat insertion allele. Eight cases of 2-octapeptide repeat insertion were identified. The cases were indistinguishable from the sporadic Creutzfeldt–Jakob cases of the same molecular subtype. Western blot characterization of the prion protein in the absence of enzymatic digestion with proteinase K revealed that 2-octapeptide repeat insertion and sporadic Creutzfeldt–Jakob disease have distinct prion protein profiles. Interrogation of large-scale population datasets suggested the variant is of very low penetrance. The 2-octapeptide repeat insertion is at most a low-risk genetic variant. Predictive genetic testing for asymptomatic blood relatives is not likely to be justified given the low risk.