Genetic Creutzfeldt-Jakob Disease Research Articles

Roving Eye and Head in a Patient With Genetic Creutzfeldt-Jakob Disease.

Roving Eye and Head in a Patient With Genetic Creutzfeldt-Jakob Disease.

Selective Vulnerability to Neurodegenerative Disease: Insights from Cell Type-Specific Translatome Studies.

Neurodegenerative diseases (NDs) manifest a wide variety of clinical symptoms depending on the affected brain regions. Gaining insights into why certain regions are resistant while others are susceptible is vital for advancing therapeutic strategies. While gene expression changes offer clues about disease responses across brain regions, the mixture of cell types therein obscures experimental results. In recent years, methods that analyze the transcriptomes of individual cells (e.g., single-cell RNA sequencing or scRNAseq) have been widely used and have provided invaluable insights into specific cell types. Concurrently, transgene-based techniques that dissect cell type-specific translatomes (CSTs) in model systems, like RiboTag and bacTRAP, offer unique advantages but have received less attention. This review juxtaposes the merits and drawbacks of both methodologies, focusing on the use of CSTs in understanding conditions like amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Alzheimer's disease (AD), and specific prion diseases like fatal familial insomnia (FFI), genetic Creutzfeldt-Jakob disease (gCJD), and acquired prion disease. We conclude by discussing the emerging trends observed across multiple diseases and emerging methods.

Factors influencing the survival period in patients with V180I genetic Creutzfeldt-Jakob disease

Factors influencing the survival period in patients with V180I genetic Creutzfeldt-Jakob disease

Short incubation periods of atypical H-type BSE in cattle with EK211 and KK211 prion protein genotypes after intracranial inoculation.

In 2006, a case of atypical H-type BSE (H-BSE) was found to be associated with a germline mutation in the PRNP gene that resulted in a lysine substitution for glutamic acid at codon 211 (E211K). The E211K amino acid substitution in cattle is analogous to E200K in humans, which is associated with the development of genetic Creutzfeldt-Jakob disease (CJD). In the present study, we aimed to determine the effect of the EK211 prion protein genotype on incubation time in cattle inoculated with the agent of H-BSE; to characterize the molecular profile of H-BSE in KK211 and EK211 genotype cattle; and to assess the influence of serial passage on BSE strain. Eight cattle, representing three PRNP genotype groups (EE211, EK211, and KK211), were intracranially inoculated with the agent of H-BSE originating from either a case in a cow with the EE211 prion protein genotype or a case in a cow with E211K amino acid substitution. All inoculated animals developed clinical disease; post-mortem samples were collected, and prion disease was confirmed through enzyme immunoassay, anti-PrPSc immunohistochemistry, and western blot. Western blot molecular analysis revealed distinct patterns in a steer with KK211 H-BSE compared to EK211 and EE211 cattle. Incubation periods were significantly shorter in cattle with the EK211 and KK211 genotypes compared to the EE211 genotype. Inoculum type did not significantly influence the incubation period. This study demonstrates a shorter incubation period for H-BSE in cattle with the K211 genotype in both the homozygous and heterozygous forms.

Sensory disturbances in Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disease characterized by rapidly progressive dementia, motor impairments, and psychiatric symptoms. Sensory disturbances were occasionally reported as well. The study aims to describe the sensory symptoms of the disease. The CJD Israeli National Database was screened for patients who presented sensory symptoms throughout the disease course. Symptoms, characteristics, and distribution were reviewed and the demographic and clinical data (sex, etiologies of the disease, age of onset, disease duration, neurological exam finding, tau protein level, EEG and MRI findings) were compared with the demographics and clinical data of CJD without sensory symptoms. Then, the patients with sensory symptoms were divided into patients with symptom distribution consistent with peripheral nervous system (PNS) involvement and central nervous system (CNS) involvement. The demographics and clinical data of the 2 groups were compared. Eighty-four CJD patients with sensory symptoms and 645 CJD patients without sensory symptoms were included in the study. Sensory symptoms were more common in genetic E200K CJD patients (14.6% vs. 5.6% respectively, p = 0.0005) (chi-squared test). Numbness and neuropathic pain were the most common symptoms and distribution of symptoms of "stocking gloves" with decreased deep tendon reflexes suggesting peripheral neuropathy in 44% of the patients. In these patients, the classical EEG findings of Periodic Sharp Wave Complexes were less often found (58% vs. 22%, p = 0.02) (chi-squared test). Sensory symptoms are more common in E200K patients and often follow peripheral neuropathy distribution that suggests PNS involvement.

Altered properties of amyloidogenic prion protein in genetic Creutzfeldt-Jakob disease with PRNP V180I mutation in response to pentosan polysulfate.

Genetic Creutzfeldt-Jakob disease (gCJD) with V180I prion protein gene (PRNP) mutation shows weaker prion protein (PrP) deposition histologically compared with sporadic CJD, and it is more difficult to detect protease-resistant prion protein in immunoblotting. However, we previously reported the autopsy case of a patient with V180I gCJD who was treated with pentosan polysulfate sodium (PPS); this case had increased protease-resistant PrP deposition. It has been suggested that PPS might reduce protease-resistant PrP; however, the detailed pharmacological and histopathological effects of PPS in humans remain unknown. We examined autopsied human brain tissue from four cases with V180I gCJD that were added to our archives between 2011 and 2021: two cases treated with PPS and two cases without PPS. We conducted a neuropathological assessment, including immunohistochemistry for PrP. We also performed immunoblotting for PrP on homogenate samples from each brain to detect protease-resistant PrP using both a conventional procedure and size-exclusion gel chromatography for the purification of oligomeric PrP. Both PPS-treated cases showed long survival time over 5 years from onset and increased PrP deposition with a characteristic pattern of coarse granular depositions and congophilic PrP microspheres, whereas the cases without PPS showed around 1-year survival from onset and relatively mild neuronal loss and synaptic PrP deposition. Although cortical gliosis seemed similar among all cases, aquaporin 4-expression as a hallmark of astrocytic function was increased predominantly in PPS cases. Immunoblotting of non-PPS cases revealed protease-resistant PrP in the oligomeric fraction only, whereas the PPS-treated cases showed clear signals using conventional procedures and in the oligomeric fraction. These unique biochemical and histopathological changes may reflect the progression of V180I gCJD and its modification by PPS, suggesting the possible existence of toxic PrP-oligomer in the pathophysiology of V180I gCJD and beneficial effects of PPS toward the aggregation and detoxication of toxic PrP-oligomer.

Spontaneous prion disease in homozygous and heterozygous transgenic mouse models of T188K genetic Creutzfeldt-Jakob disease

Genetic Creutzfeldt-Jakob disease with T188K mutation (T188K gCJD) is the most frequent genetic prion disease in China. To explore the penetration of T188K mutation and the pathogenesis of T188K gCJD, we constructed 2 lines of transgenic mouse models: homozygous Tg188K+/+ mice containing T188K mutation in 2 alleles of human PRNP background and heterozygous Tg188K+/- mice containing 1 allele of T188K human PRNP and 1 allele of the wild-type mouse PRNP. Spontaneous neurological illnesses were identified in all Tg188K mice at their old ages (750–800 days old). About half of the Tg188K mice died prior to the final observation (930 days old). Extensive spongiosis, PrPSc deposit, and reactive gliosis of astrocytes and microglia are neuropathologically identified, showing time-dependent exacerbation. Proteinase K-resistant PrP was detected in the brain, muscle, and intestine tissues, and positive real-time quaking-induced conversion reactions were elicited by the brain and muscle tissues of Tg188K mice. Those data verify that the constructed Tg188K mice highly mimic the clinicopathology of human T188K gCJD, strongly indicating the pathogenicity of T188K mutated PrP.

Thalamic‐insomnia phenotype in genetic E200K Creutzfeldt‐Jakob disease: A PET/MRI study

AbstractBackgroundInsomnia and thalamic involvement are hallmarks of fatal familial insomnia; however, it was occasionally reported that genetic E200K Creutzfeldt‐Jakob disease (CJD) patients had also manifested thalamic‐insomnia phenotype. The study aimed to explore the clinical and neuroimage characteristics of genetic E200K CJD by comprehensive neuroimage analysis.MethodsSix genetic CJD patients carried Glu to Lys change at codon 200 (E200K) mutations on prion protein gene (PRNP), thirteen sporadic CJD (sCJD), and twenty‐two age‐ and sex‐matched normal controls were enrolled in the study. All participants completed hybrid positron emission tomography/ magnetic resonance imaging (PET/MRI) examinations. The high signal was visually inspected on diffusion weighted imaging (DWI) sequence. 18F‐fluorodeoxyglucose positron emission tomography (18F‐FDG‐PET) and structural images were quantitively analyzed by statistically parameter mapping (SPM). Clinical and image characteristics are compared between genetic E200K CJD patients and sporadic CJD patients.ResultsThere was no group difference in age (49.0±7.1 versus 55.0±4.9 versus 52.7±7.3, p = 0.193) and gender (3/3 versus 4/9 versus 11/11, p = 0.513) between genetic E200K CJD, sCJD, and normal controls. Insomnia was the main complaint in the genetic E200K CJD patients’ group (4/2 versus 1/12, p = 0.007). Hyperintensity, hypometabolism but not predominant atrophy of the thalamus was found by visual inspection in genetic E200K CJD patients. A decreased trend was found on gray matter volume (uncorrected p<0.0001) and metabolism (FWE corrected) of the thalamus in genetic E200K patients.ConclusionThe clinical and image characteristics of genetic E200K CJD mimic fatal familial insomnia, manifested as a thalamic‐insomnia phenotype, indicating some specific underlying pathological changes might exist in E200K mutations. PET measurement is a sensitive approach to help identify the functional changes of the thalamus in prion disease.

A longitudinal 18F‐FDG PET study in asymptomatic stage of genetic Creutzfeldt–Jakob disease

AbstractBackgroundPathogenic prion protein may start to deposit in some brain regions and cause functional alterations in the asymptomatic stages in Creutzfeldt–Jakob disease patients. However, the disease trajectory of Creutzfeldt–Jakob disease in the asymptomatic stage and when and where the degenerative process begins are still not clear.MethodsAt baseline, we enrolled five asymptomatic mutation carriers, six affected genetic Creutzfeldt–Jakob diseasepatients, and 23 healthy controls from whom 18F fluorodeoxyglucose‐positron emission tomography, clinical, and neuropsychological measures were acquired. Only five asymptomatic mutation carriers had completed longitudinal follow‐up. We set three‐time points to identify the changing trajectory in asymptomatic carriers group including baseline, 2‐year and 4‐year follow‐up.ResultsAt baseline, the cerebral glucose metabolic rate, measured as the standardized uptake value rate ratio, clinical and neuropsychological scales in all 5 asymptomatic cases were normal. In the 4‐years follow‐up, hypometabolic brain regions in asymptomatic genetic Creutzfeldt–Jakob disease group were found in the insula, frontal, parietal, and temporal lobes (false discovery rate corrected p<0.01). The standardized uptake value rate ratio changing trajectories of all asymptomatic cases were within the range between the healthy controls and affected patients. Notably, the metabolism values of one asymptomatic individual whose baseline age was older than the expected age of onset showed a rapid decline and approached the mean value of genetic Creutzfeldt–Jakob disease condition at the last follow‐up.ConclusionOur study illustrates that neurodegenerative process associated with genetic Creutzfeldt–Jakob disease may involve the insula, frontal, temporal, and parietal lobes before clinical presentation of the disease, and the decline will accelerate when close to the expected age of onset. Although there are no effective means to cure this fatal disease, the time interval before clinical disease onset may aid important trials or therapies intended to slow or halt the disease process.

The epidemiological and clinical characteristics of patients with young-onset genetic Creutzfeldt-Jakob disease

ABSTRACT Objectives The onset of Creutzfeldt-Jakob disease (CJD) is usually around the age of 60, but younger patients have been described as well. Our study characterizes the demographic and clinical features of young-onset CJD patients. Methods The CJD Israeli National Database was reviewed, and the patients were divided into groups of young (<40-year-old) (Y|) and older disease onset (>40-year-old) (O). Each group was further divided into sporadic (sCJD) and genetic (gCJD) patients. Clinical and demographic parameters were compared between the groups Results The study included 731 patients (Y- 18 patients, O- 713 patients). MRI showed classical features more often in the older population (O-76.9%, Y-36%, p = 0.006). Rapidly progressive dementia as a presenting feature was more common in the older group (O = 58%, Y = 27.7%, p = 0.019) whereas cerebellar onset (gait instability, dysarthria) was more common in the younger group (O = 6.7%, Y = 27.7%, p = 0.036)). Among gCJD patients, rapidly progressive dementia was commonly seen in older patients (O = 54%, Y = 21% p = 0.008) whereas cerebellar symptoms were seen in young patients (O = 7%, Y = 30% p = 0.01) Typical MRI findings were seen in 37% of young people compared to 87% of older patients (p = 0.002). No significant differences were between young and older patients in the sCJD group. Conclusion Young-onset gCJD patients have unique disease features including less typical brain MRI changes, a lower prevalence of dementia, and a higher prevalence of cerebellar signs at disease onset.

Cerebral cortex swelling in V180I genetic Creutzfeldt–Jakob disease: comparative imaging study between sporadic and V180I genetic Creutzfeldt–Jakob disease in the early stage

ABSTRACT The most common genetic Creutzfeldt-Jakob disease (gCJD) in Japan is caused by a point mutation in which isoleucine replaces valine at codon 180 of the prion protein (PrP) gene (V180I gCJD). Evidence suggests that cerebral cortex swelling, which appears as abnormal hyperintensities on diffusion-weighted imaging (DWI), is a characteristic magnetic resonance imaging (MRI) finding of V180I gCJD. However, no study has directly compared the MRI findings between V180I gCJD and sporadic CJD (sCJD). The current study, therefore, aims to clarify the imaging features of V180I gCJD, which would lead to prompt genetic counselling and analysis of the PrP gene, particularly focusing on cerebral cortex swelling. We included 35 patients with sCJD (n = 23) or V180I gCJD (n = 12). Cerebral cortex swelling on T2-weighted imaging (T2WI) or fluid-attenuated inversion recovery (FLAIR) wherein abnormal cortical hyperintensities were observed on DWI, and the distribution of grey matter hyperintensities on DWI were visually evaluated. V180I gCJD patients had significantly more cerebral cortex swelling (100% vs. 13.0%, p < 0.001), an overall correct classification of 91.4%, and parahippocampal gyrus hyperintensities on DWI (100% vs. 39.1%, q = 0.019) than sCJD patients. Cerebral cortical hyperintensities on DWI with swelling on T2WI or FLAIR are characteristic imaging findings of V180I gCJD and are useful for differentiating it from sCJD.

Genetic Creutzfeldt‒Jakob disease with 5-octapeptide repeats presented as frontotemporal dementia

The N-terminus of the PRNP gene normally contains a 5-octapeptide repeat (R1-R2-R2-R3-R4), and insertions at this locus can cause hereditary prion diseases. In the present study, we found a 5-octapeptide repeat insertion (5-OPRI) in a sibling case of frontotemporal dementia. Consistent with previous literature, 5-OPRI rarely met the diagnostic criteria for Creutzfeldt‒Jakob disease (CJD). We propose 5-OPRI as a suspected causative mutation for early-onset dementia, especially the frontotemporal type.

Systematic Review of Clinical and Pathophysiological Features of Genetic Creutzfeldt-Jakob Disease Caused by a Val-to-Ile Mutation at Codon 180 in the Prion Protein Gene.

Genetic Creutzfeldt-Jakob disease (gCJD) is a subtype of genetic prion diseases (gPrDs) caused by the accumulation of mutated pathological prion proteins (PrPSc). gCJD has a phenotypic similarity with sporadic CJD (sCJD). In Japan, gCJD with a Val to Ile substitution at codon 180 (V180I-gCJD) is the most frequent gPrD, while the mutation is extremely rare in countries other than Japan and Korea. In this article, we aim to review previously elucidated clinical and biochemical features of V180I-gCJD, expecting to advance the understanding of this unique subtype in gCJD. Compared to classical sCJD, specific clinical features of V180I-gCJD include older age at onset, a relatively slow progression of dementia, and a lower positivity for developing myoclonus, cerebellar, pyramidal signs, and visual disturbance. Diffuse edematous ribboning hyperintensity of the cerebral cortex, without occipital lobes in diffusion-weighted magnetic resonance imaging, is also specific. Laboratory data reveal the low positivity of PrPSc in the cerebrospinal fluid and periodic sharp wave complexes on an electroencephalogram. Most patients with V180I-gCJD have been reported to have no family history, probably due to the older age at onset, and clinical and biochemical features indicate the specific phenotype associated with the prion protein gene mutation.

Biochemical and Neuropathological Findings in a Creutzfeldt-Jakob Disease Patient with the Rare Val180Ile-129Val Haplotype in the Prion Protein Gene.

Genetic Creutzfeldt–Jakob disease (gCJD) associated with the V180I mutation in the prion protein (PrP) gene (PRNP) in phase with residue 129M is the most frequent cause of gCJD in East Asia, whereas it is quite uncommon in Caucasians. We report on a gCJD patient with the rare V180I-129V haplotype, showing an unusually long duration of the disease and a characteristic pathological PrP (PrPSc) glycotype. Family members carrying the mutation were fully asymptomatic, as commonly observed with this mutation. Neuropathological examination showed a lesion pattern corresponding to that commonly reported in Japanese V180I cases with vacuolization and gliosis of the cerebral cortexes, olfactory areas, hippocampus and amygdala. PrP was deposited with a punctate, synaptic-like pattern in the cerebral cortex, amygdala and olfactory tract. Western blot analyses of proteinase-K-resistant PrP showed the characteristic two-banding pattern of V180I gCJD, composed of mono- and un-glycosylated isoforms. In line with reports on other V180I cases in the literature, Real-Time Quaking Induced Conversion (RT-QuIC) analyses did not demonstrate the presence of seeding activity in the cerebrospinal fluid and olfactory mucosa, suggesting that this haplotype also may result in a reduced seeding efficiency of the pathological PrP. Further studies are required to understand the origin, penetrance, disease phenotype and transmissibility of 180I-129V haplotype in Caucasians.

Genetic Creutzfeldt-Jakob disease in Turkish Jews-demographic and clinical features.

The largest cluster of genetic Creutzfeldt- Jakob Disease (CJD) exists in Libyan Jews carrying the E200K mutation in the PRNP gene. However, there is another cluster of genetic CJD with E200K mutation in families of Turkish-Jewish origin. In this retrospective study, we aim to describe the demographic and clinical features of this population of patients. The Israeli National CJD database was searched for demographic, clinical, imaging, and laboratory data of genetic CJD patients of Libyan and Turkish ancestry with the E200K mutation. The data of Libyan and Turkish patients were compared with notice similar or different demographic or clinical courses. Four hundred and twenty-three patients with CJD of Libyan (L) ancestry and 27 patients with CJD of Turkish (T) ancestry were identified. There were no significant differences in demographic and clinical data between the two populations (age of onset: T=62 ± 8.8, L=60 ± 9.7; age of death: T=63 ± 8.6, L=61 ± 9.7; and disease duration: T=7.8 ± 8.4 months, L=9.6 ± 13.6 months). Rapidly progressive dementia was the most common presentation in both groups, followed by pure cerebellar onset. The levels of tau protein in CSF did not differ between groups (T=1290 ± 397.6 pg/ml, L=1276 ± 594.2 pg/ml). MRI and EEG showed classical CJD features in most patients in both groups. The E200K mutation is the most common mutation among gCJD patients and was reported in different ethnical populations, suggesting several independent haplotypes of the mutation. The Turkish-Jew cluster, first described in this study, shares similar demographic and clinical features with the bigger cluster of Libyan-Jews CJD patients. E200K gCJD patients of Turkish ancestry share similar demographic and clinical features to patients of Libyan descent, suggesting a common origin of both populations.

A longitudinal 18F-FDG PET/MRI study in asymptomatic stage of genetic Creutzfeldt–Jakob disease linked to G114V mutation

BackgroundPathogenic prion protein may start to deposit in some brain regions and cause functional alterations in the asymptomatic stage in Creutzfeldt–Jakob disease. The study aims to determine the trajectory of the brain metabolic changes for prion protein diseases at the preclinical stage.MethodsAt baseline, we enrolled five asymptomatic PRNP G114V mutation carriers, six affected genetic PRNP E200K CJD patients and 23 normal controls. All participants completed clinical, diffusion-weighted imaging (DWI) and 18F fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) examinations. Longitudinal follow-up was completed in five asymptomatic mutation carriers. We set three-time points to identify the changing trajectory in the asymptomatic carriers group including baseline, 2-year and 4-year follow-up.ResultsAt baseline, DWI signals, the cerebral glucose standardized uptake value rate ratio (SUVR) and clinical status in 5 asymptomatic cases were normal. At the follow-up period, mild hypometabolism on PET images was found in asymptomatic carriers without any DWI abnormal signal. Further group quantitatively analysis showed hypometabolic brain regions in the asymptomatic genetic CJD group were in the insula, frontal, parietal, and temporal lobes in 4-year follow-up. The SUVR changing trajectories of all asymptomatic cases were within the range between the normal controls and affected patients. Notably, the SUVR of one asymptomatic individual whose baseline age was older showed a rapid decline at the last follow-up.ConclusionsOur study illustrates that the neurodegenerative process associated with genetic CJD may initiate before the clinical presentation of the disease.

Clinical and prognostic features of Heidenhain variant of Creutzfeldt−Jakob disease: A retrospective case series study

Heidenhain variant of Creutzfeldt-Jakob disease (CJD) remains a diagnostic challenge in clinical practice. We aimed to describe the clinical and prognostic features of Heidenhain cases, through a case series study. We retrospectively reviewed the definite or probable CJD cases admitted to two tertiary referral university hospitals over a decade to identify Heidenhain cases and investigated their survival status by telephone follow-up. Their clinical characteristics, neuroimaging features, electroencephalography (EEG) results, cerebrospinal fluid profiles, and PRNP gene mutations were also analyzed. Of a total of 85 CJD cases, 20 (24%) Heidenhain cases (11 women [55%]; median age, 64years [range, 44-72years]) were identified. The median survival time was 22weeks (range, 5-155weeks). The median duration of isolated visual symptoms was 3weeks (range, 1-12weeks). The most common early visual symptom was blurred vision (16/20, 80%), followed by diplopia (6/20, 30%). The prevalence significantly increased for complex visual hallucination (p=0.005) and cortical blindness (p=0.046) as the disease progressed. The positive rate of serial magnetic resonance images (20/20, 100%) was higher than that of serial EEGs (16/20, 80%). Two patients (2/10, 20%) had pathogenic PRNP mutations, E196A and T188K, respectively. Heidenhain cases with PRNP mutations had significantly longer survival time than those without PRNP mutations (p=0.047). Besides blurred vision (80%), diplopia (30%) was also a frequent early visual symptom among Heidenhain cases. Heidenhain phenotype can occur in genetic CJD cases. PRNP mutation status might be an important prognostic factor for Heidenhain cases.

Methionine homozygosity for PRNP polymorphism and susceptibility to human prion diseases

BackgroundNo studies have assessed the independent association of methionine homozygosity at codon 129 with the susceptibility to prion diseases, controlling for the effects of the codon 219 polymorphisms and other...

The review on: “Creutzfeldt-Jakob disease”

This review will explore the information about Creutzfeldt -Jakob disease (CJD), which is the human prion disease. CJD is a rare brain disorder and rapidly progressive. CJD belongs to the family of human prion disease, which is caused by misfolded, transmissible infections particles, or prions. Transmissible spongiform encephalopathy (TSEs), also known as prion disease. Spongiform refers to the characteristic appearance of infected brains. CJD affects about one person in every one million people per year worldwide. CJD is a fatal neurodegenerative disorder which is having a higher mortality rate. CJD usually appears in later life and has a high incubation period but become rapidly progressive once clinically symptoms begin. CJD exist in three major groups sporadic CJD (sCJD), Acquired CJD, and Genetic CJD. The sporadic form generally affects the late middle age or elderly persons (Mean age of 67 years). Most people with clinically diagnosed CJD die within a year. Other neurodegenerative illness like Alzheimer's disease involves the deposition of an aberrantly folded protein: although CJD is transmissible. There is no specific treatment for CJD except for supportive care. The arrangement of different clinicians and surveillance programs can maintain awareness of CJD to control the future incidence of its transmission.

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.