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This article presents a clinical case of Gerstmann–Sträussler–Scheinker syndrome (GSS) – a progressive inherited prion disease with an extremely rare phenotype that changed dynamically during the course of the disease and eventually led to the misdiagnosis of a motor neurone disease. An important feature of this case is a progressive myelopathy, probably due to the deposition of prion protein plaques, with the development of symptoms of lower motor neuron involvement (muscle atrophy, areflexia, fasciculations and muscle hypotonia). Clinical, laboratory, electrophysiological and neuroradiological features of this case are presented. The final diagnosis was verified by whole-exome sequencing – a typical mutation p.P102L in the prion protein gene PRNP was identified. It is discussed whether GSS should be included in the differential diagnosis in patients with progressive motor disorders, a family history and unchanged long nerve conduction function according to electromyography.

Among the numerous transmissible spongiform encephalopathies (TSEs), bovine spongiform encephalopathy (BSE) is the most well-known TSEs. It is a potential Creutzfeldt–Jakob (CJD) disease mutation that can be transferred through cattle to humans. In several animals, the prion protein gene (PRNP) is recognized to take active part in TSE vulnerability or tolerance. Previous studies have found indels polymorphism in PRNP gene promoter and intron1 region linked to BSE vulnerability. It's linked with 23 bp indels polymorphism in putative promoter and 12 bp indel in intron 1 of the PRNP gene. The aim of this study was to compare the allele, genotype and haplotype frequencies of PRNP indel polymorphisms in Zhongdian Yak (Bos grunniens) (YK), Zhongdian Yellow cattle (Bos taurus) (YC) and Zhongdian Yakow (Bos primigenius taurus × Bos grunniens) (PK) with worldwide reported healthy or affected BSE cattle, in order to assess their potential resistance to BSE. A comparison of Chinese bovine populations with healthy and BSE-affected German and Swiss cattle from globally was conducted, and result indicating significant difference (p <.001) between healthy and affected cattle. Additionally, as compared to prior studies with Chinese bovine population, the significant results were found. In this study, the allelic frequency D23 finding high deletion in all analyzed Chinese bovine species, and haplotype D12–D23 exhibited a less significant inclination toward susceptibility to BSE. [ABSTRACT FROM AUTHOR]

Simple Summary: Bovine spongiform encephalopathy (BSE), a neurological disorder with a significant effect on cattle health, has been recognized pathologically and medically. It is associated with a 12 bp indel in intron 1 of the PRNP gene and a 23 bp indel polymorphism in the putative promoter. The main focus of this work was to assess the allele, genotype, and haplotype frequencies of PRNP indel polymorphisms in Zhongdian Yak, Zhongdian Yellow cattle, and Zhongdian Yakow, as well as to investigate the effect of PRNP gene expressions of 23 bp and 12 bp indels using PCR. Two variable sites—a 23 bp indel polymorphism holding AP1 binding site and a 12 bp indel polymorphism holding SP1 binding site—were also investigated. Overall, the study results suggest that the PRNP genotype may contribute to the high variation in PRNP expression. Bovine spongiform encephalopathy (BSE) is a fatal disease in cattle caused by misfolded prion proteins and linked to indel polymorphisms in the promoter and intron 1 of the PRNP gene. The aim of this study was to determine the allele, genotype, and haplotype frequencies of PRNP indel polymorphisms and to investigate the effect of PRNP gene expressions of 23 bp and 12 bp indels via polymerase chain reaction (PCR) in Zhongdian Yak (Bos-grunniens) (YK), Zhongdian Yellow cattle (Bos-taurus) (YC), and Zhongdian Yakow (Bos-primigenius taurus × Bos-grunniens) (PK). Resultant high allelic frequencies were found in 23− and 12+, while haplotype frequencies were very low in 23+/12 in YK, YC, and PK. PRNP expression was higher in the +−/−− diplotype of the PK and (mean ± SE) was 3.6578 ± 1.85964. Furthermore, two variable sites were investigated—a 23 bp indel polymorphism holding AP1 binding site and a 12 bp indel polymorphism holding SP1 binding site. Additionally, reporter gene assays revealed a link between two proposed transcription factors and lower expression levels of the +/+ allele compared with the −/− allele. The expression level of PRNP was shown to be dependent on two indel polymorphisms in the bovine PRNP promoter, which includes binding sites for RP58 and SP1 transcription factors. These findings raised the possibility that the PRNP genotype may contribute to the high variation in PRNP expression. [ABSTRACT FROM AUTHOR]

Background: Gerstmann Sträussler Scheinker (GSS) is an inherited, invariably fatal prion disease. Like other human prion diseases, GSS is caused by missense mutations in the prion protein (PrP) gene (PRNP), and by the formation and overtime accumulation of the misfolded, pathogenic scrapie PrP (PrPSc). The first mutation identified in the PRNP gene, and the one blamed as the main cause of the disease, is c.C305T:p.P102L. Methods and results: The Sanger sequencing method was performed on the PRNP gene for the detection of c.C305T:p.P102L mutations in a cohort of 10 subjects; moreover, a study was carried out, using Next Generation Sequencing (NGS), by sequencing a group of genes related to amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), movement disorders and dementia which show a phenotypic profile similar to that of GSS. The results obtained from the study using NGS indicate the potential role of other genetic variants which could contribute to the various GSS phenotypes. Conclusions: In conclusion, we highlight the large clinical variability in subjects presenting with GSS and p.P102L, as well as the hypothesis that the mutation in PrP codon 102 alone is not sufficient to trigger the cardinal clinical signs of the disease; furthermore, we do not exclude the possibility that further genetic variants play a decisive role in the aspects of the various phenotypes with which GSS manifests itself. [ABSTRACT FROM AUTHOR]

Prion diseases are a type of neurodegenerative disorder caused by the transmission of specific pathogens containing prion proteins. Due to the unique structural characteristics of Prion proteins (PrP), which differ from other types of proteins, the extended incubation period observed in the transmission of specific Prions can be attributed to these differences, at least in part. Prions are found in several other mammals and animals. Prions are unique among false protein folding abnormalities because these are infections and contain various strains of contagious agents associated with a unique in vivo phenotype. They can be acquired either by inheritance or sporadically. There are two types: classical and typical BSP. The objective of this study was to observe the Bhagnari cattle breed of Balochistan, Pakistan and compare the PrP gene sequence of the Bhagnari with other reported sequences from Pakistan and other parts of the world. This research collected 40 Bhagnari cattle blood samples from Tali, Bhag Nari, and Sibi district areas. DNA extraction of each sample was performed by inorganic method, and then DNA amplification and sequencing of PRNP Gene was performed. The results of this research work showed different polymorphic variations (SNPs) in 16 samples. In this study, while mutations causing prion diseases in cattle were detected in Italian and German breeds, none were identified in the PRNP gene of the cattle population investigated, despite its association with neurological disorders. [ABSTRACT FROM AUTHOR]

Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare genetic prion disease caused by a mutation in the prion protein (PRNP) gene. It is typically characterized by progressive cerebellar ataxia and slowly progressive dementia. We present a case study of the GSS from China in which a 45-year-old male with a progressive gait and balance disorder developed cerebellar ataxia onset but was misdiagnosed as spinocerebellar ataxia (SCA) for 2 years. The patient's clinical, electrophysiological, and radiological data were retrospectively analyzed. Examination revealed ataxia, dysarthria,muscle weakness, areflexia in lower limbs, including a pyramidal sign, whereas cognitive decline was insignificant. His late mother had a similar unsteady gait. An electroencephalogram (EEG) showed normal findings, and 14-3-3 protein was negative. A brain MRI was performed for global brain atrophy and ventricular enlargement. Positron emission tomography-- computed tomography (PET--CT) (18F-fluoro-2-deoxy-d-glucose, FDG) images showed mild to moderate decreased glucose metabolism in the left superior parietal lobe and left middle temporal lobe. According to genetic testing, his younger brother also had the P102L variant in the PRNP gene. This single case adds to the clinical and genetic phenotypes of GSS. [ABSTRACT FROM AUTHOR]

Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative diseases with a chronic and fatal course, which are caused by a misfolded form of the cellular prion protein that is encoded by the host. The purpose of this work was to evaluate the resistance and genetic susceptibility to prion diseases in Pelibuey sheep from Mexico. The sequences of 99 Pelibuey sheep from the central and southwestern regions of Mexico were analyzed to determine the polymorphisms related to resistance and genetic susceptibility to scrapie, the Hardy-Weinberg equilibrium test and the D-Tajima test was used to identify the effect of evolutionary forces on the PRNP gene. Twelve non-synonymous polymorphisms Q101R, M112T, A116P, G127A, A136V, M137T, L141F, H143R, R154H, Q171R, Q171H, N176K were detected, in addition two synonymous substitutions 231R (agg/cgg) and 237L (ctc/ctg) were found. As a result of the sequence analysis, the ARR allele was not under the Hardy-Weinberg equilibrium, indicating that there is an evolutionary force at work, and the D-Tajima suggest the existence of purifying genetic selection. In conclusion, Pelibuey sheep exhibit genotypes for the PRNP gene that make them resistant to developing classic scrapie; at least 98% of the population is a carrier of an allele related to scrapie resistance; while for atypical scrapie there is a very high probability that an outbreak occurred in the herds, since the ARQ allele in combination with the L substitution at codon 141 confers susceptibility to carrier sheep.

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.

ABSTRACT: Bovine spongiform encephalopathy (BSE) is a transmissible progressive neurodegenerative disease characterized by the accumulation of a pathological isoform (PrpSC) of the cellular prion protein (PrpC) in the brain of cattle. Two insertion/deletion polymorphisms in the PRNP gene (23bp in the promoter and 12bp in intron 1) have been associated with resistance or susceptibility to the disease. The aim of this study was to analyze the distribution of these polymorphisms in 214 healthy bovines belonging to four different breed groups (Aberdeen Angus, Aberdeen Angus x Hereford, Holstein Friesian and Uruguayan Creole cattle). DNA samples were amplified by end-point PCR. A high frequency of the alleles and haplotype associated with susceptibility to BSE (del12 and del23, and del12-del23, respectively) were found in the Aberdeen Angus, Aberdeen Angus x Hereford and Holstein Friesian animals. At the same time, the Uruguayan Creole cattle presented a higher frequency of the alleles and haplotype associated with resistance to BSE (ins12 and ins23, and ins12-ins23, respectively). These data could indicate a greater genetic resistance of the Uruguayan Creole cattle to BSE compared to other analyzed breeds, reinforcing its value as a zoogenetic resource.

Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative diseases with a chronic and fatal course, which are caused by a misfolded form of the cellular prion protein that is encoded by the host. The purpose of this work was to evaluate the resistance and genetic susceptibility to prion diseases in Pelibuey sheep from Mexico. The sequences of 99 Pelibuey sheep from the central and southwestern regions of Mexico were analyzed to determine the polymorphisms related to resistance and genetic susceptibility to scrapie, the Hardy-Weinberg equilibrium test and the D-Tajima test was used to identify the effect of evolutionary forces on the PRNP gene. Twelve non-synonymous polymorphisms Q101R, M112T, A116P, G127A, A136V, M137T, L141F, H143R, R154H, Q171R, Q171H, N176K were detected, in addition two synonymous substitutions 231R (agg/cgg) and 237L (ctc/ctg) were found. As a result of the sequence analysis, the ARR allele was not under the Hardy-Weinberg equilibrium, indicating that there is an evolutionary force at work, and the D-Tajima suggest the existence of purifying genetic selection. In conclusion, Pelibuey sheep exhibit genotypes for the PRNP gene that make them resistant to developing classic scrapie; at least 98% of the population is a carrier of an allele related to scrapie resistance; while for atypical scrapie there is a very high probability that an outbreak occurred in the herds, since the ARQ allele in combination with the L substitution at codon 141 confers susceptibility to carrier sheep. [ABSTRACT FROM AUTHOR]

Bovine spongiform encephalopathy (BSE) is a fatal disease in cattle caused by misfolded prion proteins and linked to indel polymorphisms in the promoter and intron 1 of the PRNP gene. The aim of this study was to determine the allele, genotype, and haplotype frequencies of PRNP indel polymorphisms and to investigate the effect of PRNP gene expressions of 23 bp and 12 bp indels via polymerase chain reaction (PCR) in Zhongdian Yak (Bos-grunniens) (YK), Zhongdian Yellow cattle (Bos-taurus) (YC), and Zhongdian Yakow (Bos-primigenius taurus × Bos-grunniens) (PK). Resultant high allelic frequencies were found in 23− and 12+, while haplotype frequencies were very low in 23+/12 in YK, YC, and PK. PRNP expression was higher in the +−/−− diplotype of the PK and (mean ± SE) was 3.6578 ± 1.85964. Furthermore, two variable sites were investigated—a 23 bp indel polymorphism holding AP1 binding site and a 12 bp indel polymorphism holding SP1 binding site. Additionally, reporter gene assays revealed a link between two proposed transcription factors and lower expression levels of the +/+ allele compared with the −/− allele. The expression level of PRNP was shown to be dependent on two indel polymorphisms in the bovine PRNP promoter, which includes binding sites for RP58 and SP1 transcription factors. These findings raised the possibility that the PRNP genotype may contribute to the high variation in PRNP expression.

Background and purpose: Cerebral amyloid angiopathy (CAA) has been associated with a variety of neurodegenerative disorders, included prion diseases and Alzheimer's disease; its pathophysiology is still largely unknown. We report the case of an 80‐year‐old man with rapidly progressive dementia and neuroimaging features consistent with CAA carrying two genetic defects in the PRNP and SORL1 genes. Methods: Neurological examination, brain magnetic resonance imaging (MRI), electroencephalographic–electromyographic (EEG–EMG) polygraphy, and analysis of 14‐3‐3 and tau proteins, Aβ40, and Aβ42 in the cerebrospinal fluid (CSF) were performed. The patient underwent a detailed genetic study by next generation sequencing analysis. Results: The patient presented with progressive cognitive dysfunction, generalized myoclonus, and ataxia. Approximately 9 months after symptom onset, he was bed‐bound, almost mute, and akinetic. Brain MRI was consistent with CAA. CSF analysis showed high levels of t‐tau and p‐tau, decreased Aβ42, decreased Aβ42/Aβ40 ratio, and absence of 14.3.3 protein. EEG–EMG polygraphy demonstrated diffuse slowing, frontal theta activity, and generalized spike‐waves related to upper limb myoclonus induced by intermittent photic stimulation. Genetic tests revealed the presence of the E270K variant in the SORL1 gene and the presence of a single octapeptide repeat insertion in the coding region of the PRNP gene. Conclusions: The specific pathogenic contribution of the two DNA variations is difficult to determine without neuropathology; among the possible explanations, we discuss the possibility of their link with CAA. Vascular and degenerative pathways actually interact in a synergistic way, and genetic studies may lead to more insight into pathophysiological mechanisms. [ABSTRACT FROM AUTHOR]

Fatal familial insomnia (FFI) is a rare genetic human prion disease with an autosomal dominant pattern of inheritance caused by a D178N mutation in the PRNP gene. FFI is characterized by a variable clinical presentation and subacute manifestation. The latter prompts to consider autoimmune encephalitis as a differential diagnosis in the diagnostically challenging patients. Here, we present a clinical case of FFI that was initially misdiagnosed with autoimmune encephalitis. A 26-year-old woman presented with rapid development of diverse neurological features, autonomic and endocrine disturbances, which initially were considered as manifestations of an autoimmune disease due to the lack of clear indications of positive family history. She was started on corticosteroids with temporary stabilization and even with a mild improvement for several months. Progressive deterioration of her symptoms with development of the psychiatric and cognitive impairment, as well as subsequently received additional information regarding positive family history, prompted us to perform a PRNP gene test that revealed a D178N mutation and confirmed an FFI diagnosis.

Creutzfeldt-Jakob disease (CJD) is an uncommon neurodegenerative disorder with an incidence of 1 per 1,000,000 in humans per year, typically characterized by rapidly progressive dementia, ataxia, myoclonus and behavioral changes. Genetic prion diseases, which develop due to a mutation in the prion protein gene (PRNP), account for an estimated 10 to 15% of all CJD cases. Familial CJD is transmitted with an autosomal dominant inheritance pattern with high penetrance. Worldwide, the most common mutation is E200K (glutamate to lysine). We report four families with CJD assisted in Neuquén Hospital in 2018. Three of the four index cases had family history of neurological and psychiatric illness, though data was not taken into consideration at the moment of evaluation of the new cases. The most significant data recorded for a genetic consultation was when the problem had started, and it was required by a neurologist. The initial symptoms were persistent insomnia and depression with poor response to habitual psychiatric medication. Impoverishment is fast with visual disorder, myoclonias, ataxia, dementia and loss of language. Pedigree analysis allowed the identification of 144persons with the gene potential, who can develop the disease at any time in their adulthood. In all cases, mutation E200K was identified. There is a region of increased frequency of CJD. There must be suspicion on patients with neuropsychiatric symptoms and suspected family history(familiar background). Finding of the mutation confirms the diagnosis in patients and allows the identification on pre-symptomatic individuals. Challenge is posed on gene advice and to avoid iatrogenic disorder transmission.

Background: Insomnia and thalamic involvement were frequently reported in patients with genetic Creutzfeldt-Jakob disease (gCJD) with E200K mutations, suggesting E200K might have discrepancy with typical sporadic CJD (sCJD). The study aimed to explore the clinical and neuroimage characteristics of genetic E200K CJD patients by comprehensive neuroimage analysis. Methods: Six patients with gCJD carried E200K mutation on Prion Protein (PRNP) gene, 13 patients with sporadic CJD, and 22 age- and sex-matched normal controls were enrolled in the study. All participants completed a hybrid positron emission tomography/magnetic resonance imaging (PET/MRI) examination. Signal intensity on diffusion-weighted imaging (DWI) and metabolism on PET were visually rating analyzed, statistical parameter mapping analysis was performed on PET and 3D-T1 images. Clinical and imaging characteristics were compared between the E200K, sCJD, and control groups. Results: There was no group difference in age or gender among the E200K, sCJD, and control groups. Insomnia was a primary complaint in patients with E200K gCJD (4/2 versus 1/12, p = 0.007). Hyperintensity on DWI and hypometabolism on PET of the thalamus were observed during visual rating analysis of images in patients with E200K gCJD. Gray matter atrophy (uncorrected p

Scrapie is a transmissible spongiform encephalopathy caused by prions and leads to neurodegeneration in the Central Nervous System (CNS) of sheep and goats. Genetic resistance/susceptibility to scrapie is well studied and it is known that the variations of 136th, 154th and 171st codons at the ovine PRNP gene have a major effect on the development of the disease. Many studies demonstrated that selection for PRNP genotypes has not influenced other performance traits, nevertheless, there is a knowledge gap about the possible link between the PRNP gene and the status of the other important diseases that affect the sheep population worldwide. In the present study, we tested whether there is an association between scrapie-related PRNP genotypes and fecal egg count (FEC) of gastrointestinal nematodes in seven adult Turkish sheep breeds. For this purpose, FEC scores of studied sheep (n = 253) were determined and the same animals were genotyped for the PRNP gene. Finally, an association analysis was performed for scrapie resistant (ARR), susceptible (VRQ), and wild-type (ARQ) haplotypes. Based on our statistical analysis, it is concluded that PRNP genotypes have no positive or negative effect on the FEC scores of adult sheep. [ABSTRACT FROM AUTHOR]

Eva Bagyinszky,1 Vo Van Giau,1 Young Chul Youn,2 Seong Soo A An,1 SangYun Kim3 1Department of Bionano Technology, Gachon Bionano Research Institute, Gachon University, Gyeonggi-do, South Korea; 2Department of Neurology, Chung-Ang University College of Medicine, Seoul, South Korea; 3Department of Neurology, Seoul National University College of Medicine & Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seongnam, South Korea Abstract: Abnormal prion proteins are responsible for several fatal neurodegenerative diseases in humans and in animals, including Creutzfeldt–Jakob disease (CJD), Gerstmann–Sträussler–Scheinker disease, and fatal familial insomnia. Genetics is important in prion diseases, but in the most cases, cause of diseases remained unknown. Several mutations were found to be causative for prion disorders, and the effect of mutations may be heterogeneous. In addition, different prion mutations were suggested to play a possible role in additional phenotypes, such as Alzheimer’s type pathology, spongiform encephalopathy, or frontotemporal dementia. Pathogenic nature of several prion mutations remained unclear, such as M129V and E219K. These two polymorphic sites were suggested as either risk factors for different disorders, such as Alzheimer’s disease (AD), variant CJD, or protease-sensitive prionopathy, and they can also be disease-modifying factors. Pathological overlap may also be possible with AD or progressive dementia, and several patients with prion mutations were initially diagnosed with AD. This review also introduces briefly the diagnosis of prion diseases and the issues with their diagnosis. Since prion diseases have quite heterogeneous phenotypes, a complex analysis, a combination of genetic screening, cerebrospinal fluid biomarker analysis and imaging technologies could improve the early disease diagnosis. Keywords: genetics, mutation, prion, PRNP gene, Creutzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker disease, fatal familial insomnia, Alzheimer’s disease, diagnosis

Creutzfeldt–Jakob disease (CJD) belongs to a group of prion disease that is caused by abnormally folded proteins and is clinically characterized by rapidly progressive cognitive decline, gait abnormalities, and myoclonus. Familial CJD is very rare and is described only in few families around the world. We report a case with rapidly progressive cognitive decline, ataxia, and myoclonus, with a history of several members of his family developing similar symptoms and succumbing to it. Clinical presentation and neuroimaging were suggestive of CJD. On genetic analysis, our index case and two of his family members (younger brother and younger son) were found to have D178N mutation in PRNP gene. The polymorphism of the 129th amino acid was V/V. We report the first kindred familial CJD from South-East Asia with genetically proven D178N-129V haplotype.

[Display omitted] • First report on Met/Met patient of FFI with postural instability and backward leaning from disease onset. • The phenotypic spectrum of homozygous FFI may be broader and more variable than previously described. • Positive anti-SOX1 in serum of FFI points the complicated association between prionopathies and immune-related factors. [ABSTRACT FROM AUTHOR]

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Abstract The misfolding of the cellular prion protein (PrPC) causes fatal neurodegenerative diseases. Yet PrPC is highly conserved in mammals, suggesting that it exerts beneficial functions preventing its evolutionary elimination. Ablation of PrPC in mice results in well-defined structural and functional alterations in the peripheral nervous system. Many additional phenotypes were ascribed to the lack of PrPC, but some of these were found to arise from genetic artifacts of the underlying mouse models. Here, we revisit the proposed physiological roles of PrPC in the central and peripheral nervous systems and highlight the need for their critical reassessment using new, rigorously controlled animal models.

Abstract: The objective of this work was to determine the genotypic profile specific to scrapie in codons 136, 154, and 171 of the PRNP gene of the Pantanal creole sheep. Genomic DNA was extracted from blood samples collected from 66 sheep, and the regions of interest on the DNA strand were amplified by PCR. Five haplotypes were identified: ARR, alanine, arginine, arginine; ARQ, alanine, arginine, glutamine; AHQ, alanine, histidine, glutamine; ARH, alanine, arginine, histidine; and VRQ, valine, arginine, glutamine. The most common genotypes were ARQ/ARQ (27%) and ARR/ARQ (24%). The genotypic profile of the Pantanal creole sheep shows low to moderate susceptibility.

The clinical presentation in Chinese patients with sporadic Creutzfeldt-Jakob disease (sCJD) may be unique due to the big difference in the codon 129 polymorphism of the prion protein gene (PRNP). This study retrospectively reviewed 26 cases of sCJD diagnosed in a single center in recent years. All 26 sCJD patients received brain magnetic resonance imaging scan, cerebrospinal fluid 14-3-3 protein detection, electroencephalogram, and PRNP gene screening. The codon 129 polymorphism were all homozygous MM in 26 sCJD patients. The main onset symptoms of sCJD patients were rapidly progressive dementia, visual impairment, and cerebellar ataxia. At the time of diagnosis, the incidence of myoclonus and akinetic mutism were relatively low (<50%). For auxiliary examinations, the positive rate of the typical magnetic resonance imaging (MRI) abnormalities, cerebrospinal fluid 14-3-3 protein, and electroencephalogram-periodic sharp wave complex was 96%, 64%, and 50%, respectively. As MM genotype is dominant and brain MRI is sensitive, brain MRI seems to play a major role in diagnosis of sCJD in Chinese. [ABSTRACT FROM AUTHOR]

Resistance to fatal disease bovine spongiform encephalopathy (BSE), due to misfolded prion protein in cattle, is associated with a 23-bp indel polymorphism in the putative promoter and a 12-bp indel in intron 1 of the PRNP gene. Gayal (Bos frontalis) is an important semiwild bovid species and of great conservation concern, but till today these indel polymorphisms have not been evaluated in gayals. Therefore, we collected 225 samples of gayals and evaluated the genetic indel polymorphism in the two regions of this PRNP gene. The results revealed high allelic frequencies of insertions at these indel sites: 0.909 and 0.667 for, respectively, the 23 bp and 12 bp indels, both also with significant genotype frequencies (χ2: 9.81; 23 bp and χ2: 43.56; 12 bp). At the same time, the haplotype data showed indel polymorphisms with extremely low deletion (0.01) in both regions of the PRNP gene. We compared these data with those reported for healthy and BSE-affected cattle (Bos taurus) breeds from two European countries, Germany and Switzerland, and significant difference (P<0.001) was observed between BSE-affected as well as the healthy cattle. Further, our data were also extensively compared with previous reports on BSE and highly significant (P<0.001) outcomes were observed. This result suggested negligible genetic susceptibility to BSE in gayals. To the best of our knowledge, this study is the first comprehensive deciphering information about the PRNP indel polymorphisms of 23 bp and 12 bp in gayals, a semiwild species of China. [ABSTRACT FROM AUTHOR]

The bovine spongiform encephalopathy (BSE), is a neurodegenerative disorder initiated by miss folded prion protein affecting in cattle. It is associated with a 23 bp indel polymorphism in the putative promoter and a 12 bp indel in intron 1 of the PRNP gene. There is no prior record of investigating for these indels polymorphism from Binglangjiang (BLJ) buffalo. The results of collected 100 samples from BLJ buffalo demonstrated that high insertion of genotype frequencies in 23++ (0.98) and 12++ (0.93) with the allelic frequencies also high in 23 bp (0.980) and 12 bp (0.965) while deletion is considerably low or absent in the allelic as well as in genotype frequencies. Haplotypes data showed different indel polymorphism with absent deletion (0) in both regions of this PRNP gene. A comparative analysis of BLJ buffalo with healthy and BSE affected German and Swiss cattle breeds from European countries was done with the results signifying a difference (P<0.001) in healthy and affected cattle. Significant outcomes were observed after comparison with previous studies on BLJ buffalo. Result demonstrated no genetic vulnerability to in BJL buffalo. Thus, BLJ buffalo can therefore prove to be the most likely model for genetic, selection, breeding and production. To best of our knowledge, this was first study describing indels polymorphism 23 bp & 12 bp in BLJ buffalo (river buffalo) of China. [ABSTRACT FROM AUTHOR]

Scrapie is a prion disease that affects the sheep and goats. It belongs to the group of transmissible spongiform encephalopathies (TSE). TSEs are characterized by the accumulation of the pathological form (PrPSc) of the cellular prion protein (PrPC). The susceptibility of sheep to scrapie is influenced by polymorphisms in the PrP gene (PRNP). The aim of this study was to identify the genetic variability of sheep PRNP in Algerian sheep. Two-hundred and thirteen Algerian sheep from eight breeds (Ouled Djellal, Rembi, Hamra, Berbere, Barbarine, Sidaou, Taadmit and Tazegzawt) with no clinical manifestation of scrapie were analysed. Sequencing of the entire coding sequence of PRNP showed four main alleles (ARQ, ARR, AHQ and ARH) based on codons 136, 154 and 171 with different frequencies among the investigated breeds. Moreover, 14 additional nonsynonymous polymorphisms (Q101R, N103K, M112T, A116P, M137I, L141F, I142M, H143R, N146S, R151G, Y172D, N176K, H180Y and S240P) as well as two synonymous polymorphisms at codons 231 and 237 were found in the PRNP gene. Interestingly, the N103K, M137I and I142M polymorphisms were not described in sheep. The ARQ, ARR and ARH haplotypes were present in all breeds with a highest frequency of ARQ in Barbarine. The ARH was absent in Barbarine breed and the VRQ haplotype was absent in all Algerian breeds studied. The ARQ and ARR alleles were the most common with frequencies ranging from 30 to 65% and from 8 to 26%, respectively, in different breeds. These results represent the first study on PRNP variability in Algerian sheep and may serve as a basis for the development of breeding programmes to render national sheep breeds resistant to scrapie. [ABSTRACT FROM AUTHOR]

The aim of the study was to examine the mediation of insulin growth factor-1 (IGF-1) in Alzheimer's disease (AD), as well as the underlying mechanism of the PRNP genetic expression and PI3K/Akt signaling pathway. The Aß25-35-incubated rat adrenal pheochromocytoma cell (PC12) in vitro was established, constituting the AD model. Different doses (0, 20, 40 and 80 ng/ml) of IGF-1 were used in PC12 cells and the level of PRNP mRNA was tested after 24 h using the quantitative PCR method and the level of APP protein was assessed using western blot analysis. PC12 cells were divided into the control group (PC12 cells without Aß25-35 treatment), model group (PC12 cells with Aß25-35 treatment), IGF-1 80 ng/ml group, IGF-1 80 ng/ml+PI3K inhibitor LY294002 25 µmol/l group, and IGF-1 80 ng/ml+LY294002 50 µmol/l group, whose PRNP mRNA level and Akt, pAkt and APP protein level were tested 24 h later. As the dose of IGF-1 increases, the expression levels of PRNP mRNA and APP protein were more highly expressed. The difference between them was significant (P<0.05). In addition, regarding Akt protein, the expression levels of PRNP mRNA, APP protein and pAkt protein in the IGF-1 groups were significantly higher than those in the control and model groups. With the LY concentration increasing, the levels of expression of the three substances gradually decreased significantly (P<0.05). In conclusion, IGF-I can mediate the expression of the PRNP gene and APP protein through the PI3K/Akt signaling pathway, in a rat model. [ABSTRACT FROM AUTHOR]

Susceptibility to 'scrapie' disease in goats is influenced by polymorphisms of the prion protein ( PRNP) gene. The aim of this study was to identify PRNP gene polymorphisms in a total of 356 scrapie disease-free goats from 10 Turkish native breeds. Eighteen single-nucleotide polymorphisms were detected in the caprine PRNP open-reading frame. Ten previously described amino acid substitutions (I142M, H143R, N146S, N146D, R151H, R154H, P168Q, R211Q, Q222K and P240S) and two novel dimorphisms (G134E and Q163P) were identified. The strongest association between caprine PRNP and relative resistance to scrapie disease has been reported previously for polymorphisms at codons 146 (S /D) and 222 (K). In the present study, these three PrP variants were relatively rare with 6.3%. This is the first report on PRNP gene variation in Turkish native goat breeds and our knowledge of these polymorphisms will assist goat breeding programmes to reduce the risk of scrapie. [ABSTRACT FROM AUTHOR]

Creutzfeldt–Jakob disease (CJD) belongs to a group of prion disease that is caused by abnormally folded proteins and is clinically characterized by rapidly progressive cognitive decline, gait abnormalities, and myoclonus. Familial CJD is very rare and is described only in few families around the world. We report a case with rapidly progressive cognitive decline, ataxia, and myoclonus, with a history of several members of his family developing similar symptoms and succumbing to it. Clinical presentation and neuroimaging were suggestive of CJD. On genetic analysis, our index case and two of his family members (younger brother and younger son) were found to have D178N mutation in PRNP gene. The polymorphism of the 129th amino acid was V/V. We report the first kindred familial CJD from South-East Asia with genetically proven D178N-129V haplotype. [ABSTRACT FROM AUTHOR]

Scrapie is a neurodegenerative disease affecting ovine and it is one of several transmissible spongiform encephalopathies (TSEs). Scrapie is recognized as two forms – classical and atypical. Susceptibility or resistance to classical scrapie is strongly regulated by the polymorphisms at codons 136, 154 and 171 of the PRNP gene. Genetic role in atypical scrapie has been described at codons 141 and 154, these ones are involved in the occurrence of the disease at different risk degrees. The aim of this study was to assess the allelic and genotypic frequencies in Sopravissana breed, an endangered autochthon breed of central Italy; in addition, the presence and the frequency of potential protective ARQ allele variants able to increase scrapie resistance by preserving a higher variability of PRNP were evaluated. Three alleles (ARQ, ARR and AHQ) and seven genotypes were observed based on codons 136, 154 and 171 with different frequencies. Moreover, the entire coding sequence of prion protein (PRNP) of the ARQ/ARQ was sequenced; two non-synonymous L141F (23.8%) and H143R (16.7%), also two synonymous polymorphisms (codons 231 and 237) were found. The results showed that the ARQ/ARQ sheep should be considered as a genetic class, which may potentially include animals with different scrapie susceptibility because of the presence of additional polymorphisms. This may allow the application of alternative strategies for breeding programmes in this endangered breed.

Gerstmann-Sträussler disease (GSD) is a very rare autosomal dominant late-onset neurodegenerative disorder related to prion protein gene PRNP . Mutation p.Pro102Leu produces about 80% of cases, which are often named GSD-102. DNA testing provides exact diagnosis. In the presented Russian family there were 3 patients: a female index case, age 32 years, her brother, age 37 years (age of onset in both is 27 years) and their deceased father (onset in 35 years, death in 44 years). GSD was not suspected until whole exome sequencing in the female detected PRNP mutation p.Pro102Leu confirmed in her and in the brother by Sanger sequencing. Atypical features of the case are: early onset in siblings, absence of mental and behavioral problems in the female and in the father and mild disturbances in the brother; epilepsy in the brother; atypical onset with transient signs in the brother. Other intrafamilial differences are prevailing spastic paraparesis in the female in contrast to predominant ataxia in the brother and dysarthria absence in the female. The case illustrates GSD-102 variability, complicating clinical diagnostics.

Scrapie is a neurodegenerative disease affecting ovine and it is one of several transmissible spongiform encephalopathies (TSEs). Scrapie is recognized as two forms – classical and atypical. Susceptibility or resistance to classical scrapie is strongly regulated by the polymorphisms at codons 136, 154 and 171 of the PRNP gene. Genetic role in atypical scrapie has been described at codons 141 and 154, these ones are involved in the occurrence of the disease at different risk degrees. The aim of this study was to assess the allelic and genotypic frequencies in Sopravissana breed, an endangered autochthon breed of central Italy; in addition, the presence and the frequency of potential protective ARQ allele variants able to increase scrapie resistance by preserving a higher variability of PRNP were evaluated. Three alleles (ARQ, ARR and AHQ) and seven genotypes were observed based on codons 136, 154 and 171 with different frequencies. Moreover, the entire coding sequence of prion protein (PRNP) of the ARQ/ARQ was sequenced; two non-synonymous L141F (23.8%) and H143R (16.7%), also two synonymous polymorphisms (codons 231 and 237) were found. The results showed that the ARQ/ARQ sheep should be considered as a genetic class, which may potentially include animals with different scrapie susceptibility because of the presence of additional polymorphisms. This may allow the application of alternative strategies for breeding programmes in this endangered breed. [ABSTRACT FROM AUTHOR]

Breeding for scrapie resistance in sheep, has being implemented in Europe as an efficient eradication policy. In goats, in contrast, the analysis on prion gene (PRNP) polymorphisms showed that some polymorphic variants can be protective for the disease but their prevalence in different breeds is still under investigation. Currently, in the presence of positive goats a complete cull of the herd is performed with a great economic loss and a serious threat of extinction for the endangered breeds. A polymorphism that seems related to caprine scrapie resistance is present at the codon 222 of the PRNP, with a lysine (K) instead of glutamine (Q) but this variant is not present in several widely diffused goat breeds in different countries. To evaluate the prevalence of the K222 variant in local goats we studied the “Girgentana ”, an endangered autochthon dairy breed. The dairy products from the milk of this breed, with an excellent balance between fat and proteins are very typical and considered a “Slow Food” presidium. The results showed that K222 variant is common in Girgentana breed (18,7%) suggesting a rapid realization of a breeding plan for scrapie resistance based on K222 allele, in contrast to commercially widely used alpine breeds such as Saanen , that have a lower prevalence of this allele. The results suggest that genetic biodiversity might be a great resource for the selection of scrapie resistance, for the conservation of endangered breeds and their typical food productions. [ABSTRACT FROM AUTHOR]

The article presents a study focusing on genetic evidence for susceptibility and resistance against scrapie disease in Indian sheep breeds including Karnah, Mandya, Malpura. The findings include the reasons for scrapie resistance in Indian sheep including inherent resistance, polymorphism protecting the animals from prion infections, and management practices of sheep rearing, the association between sheep genotype and the risk of death from scrapie, and several charts related to the same.

The aim of this study was to verify the hypothesis that insertion/deletion (indel) polymorphisms within the promoter and intron 1 sequences of the prion protein (PRNP) gene can affect the breeding value of Holstein-Friesian bulls. The experimental material included 261 Holstein-Friesian bulls born between 1997-2002. It was shown that the polymorphism in the intron 1 (12 bp indel) sequence had a more significant effect on the analyzed traits than a polymorphism in the promoter (23 bp indel) sequence. A deletion allele within intron 1 (12del) significantly increased the bulls' breeding value for milk yield (p=0.001), protein yield (p=0.042), type and conformation (p=0.018), udder width (p=0.003), dairy character (p=0.004), and decreased days open (p=0.022). A deletion allele (23del) at the polymorphic locus of the promoter significantly decreased the bulls' breeding value for milk yield (p=0.001), udder width (p=0.029) and dairy character (p=0.033). Analysis of both alleles showed that 23del-12del haplotype increased the bulls' breeding value for udder traits: udder (p=0.008), fore udder (p=0.043) and udder depth (p=0.041), and decreased for fat content (p=0.047) and conformation traits - body depth (p<0.001), chest width (p=0.029) and rear leg set - side view (p=0.029). Also positive effect of 23del-12ins haplotype for days open (p=0.003) and days between calving and first insemination (p=0.045) was observed. [ABSTRACT FROM AUTHOR]

Objective To explore the effects of phosphatidyl inositol 3-kinase (PI3K)/protein kinase B (Akt)/fork - head boxO (FoxO) signaling pathway on PRNP expression of insulin-like growth factor 1 (IGF -1) regulating nerve cells PC12. Methods PC12 cells in logarithmic phase were divided into IGF-1 group，experiment group 1，experiment group 2 and the control group. The cells in the IGF-1 group were added with 80 ng/ml IGF-1， cells in the experiment group 1 and experiment group 2 were separately added with 25 and 50 pmol/L LY294002， followed by 80 ng/ml IGF-1 after 30 min 37 ℃ cultivation. The control group was not given drugs. After 24 h of cultivation， the PRNP mRNA expression of PC12 cells was calculated by real-time fluorescent quantitative PCR in each group. The AKT phosphorylation，AKT phosphorylation (pAKT)，FoxO3a and FoxO3a (pFoxO3a) protein expression of PC12 cells was measured by Western blotting in each group. Results The PRNP mRNA and pAKT，pFoxO3a protein expression of the IGF-1 group was higher than that of the control group (all P < 0. 05). The PRNP mRNA and pAKT，pFoxO3a protein expression of experiment group 1 and experiment group 2 was lower than that of the IGF-1 group (all P < 0. 05)， and the experimental group 2 was lower than the experimental group 1 (P < 0. 05). Conclusion IGF-1 could regulate PRNP gene expression of PC12 cells through phosphorylation PI3K/Akt/FoxO signaling pathway proteins Akt and FoxO3a. [ABSTRACT FROM AUTHOR]

The hazard to human health represented by transmissible spongiform encephalopathies in sheep is one of the major reasons for implementing the genetic selection plan to break down prion diseases. The problem is particularly important because of the risk of disease transmission from ewe to lamb via milk or colostrum. In order to establish an active and convenient monitoring of the flocks already undergone genetic selection and thus, indirectly increase consumers' security, the challenge of the work was quantifying the classical scrapie risk in bulk milk. A new quantitative real-time PCR assay for the estimation of the 171 R and Q allelic frequencies in a DNA pool representative of all the lactating ewes present in a flock was optimized and validated "in field". The repeatability range was 3.69-5.27 for R and 4.20-5.75 for Q. The ruggedness of the allele frequencies resulted 4.26 for R and 4.77 for Q. Regarding the validation "in field", none of the considered sources of variability (flock, month, number of genotyped animals and somatic cell count) showed a significant effect on flock and milk at the linear model. The targeted next-generation sequencing was also tested to evaluate its applicability in this context. Results show that the real-time PCR assay could represent a valid tool for the determination of 171 R/Q allele frequencies in bulk milk. The implementation of a service for breeder self-control along the production chain would aim to increase the production of high-security dairy products, while monitoring over time of the effects of genetic selection in the flocks. [ABSTRACT FROM AUTHOR]

The cellular prion protein, encoded by Prnp gene, is involved in neuroprotection, neuroplasticity and neurodevelopment. The variant allele Valine at codon 129 of the Prnp was associated with decreased brain volume in healthy volunteers and schizophrenic patients. We investigate the association between the cerebellum volume and the presence of variant allele Valine at codon 129 of the Prnp gene in patients with mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS). The Prnp coding sequence was determined in 41 refractory MTLE-HS patients. The cerebellum volume corrected by the intracranial volume of patients with the normal Prnp genotypes was compared with that of patients presenting the variant alleles at codon 129. Twenty patients showed the Met129Met genotype, 16 showed Met129Val, and 5 had Val129Val. There were no association among clinical, demographic, electrophysiological, antiepileptic drugs used, and the presence of the Prnp variant alleles. The presence of Prnp variant allele at codon 129 was not associated with the analyzed cerebellum volume. Prnp variant alleles at codon 129 are not associated with cerebellum volume in patients with refractory MTLE-HS. [ABSTRACT FROM AUTHOR]

The purpose of this study was to analyze associations between polymorphisms in the PRNP gene and ewe milk traits. A total of 242,565 lactations of the Latxa breed were used. Milk, fat and protein yields, and fat and protein content from black-faced Latxa from Spanish Basque Country, black-faced Latxa from Navarra, and blond-faced Latxa were collected. To evaluate evidence of association, the different traits were analyzed using an animal model, where the PRNP genotype effect was included or not as a random effect. Adding the PRNP effect to the model improved the fitting for milk yield in black-faced Latxa from Spanish Basque Country and in blond-faced Latxa, for fat yield in black-faced Latxa from Navarra, and for protein yield in blond-faced Latxa. However, the proportion of the phenotypic variance explained by the PRNP effect for milk yield (1.0 x 10-3), fat yield (3.6 x 10-4) and pro tein yield (9.4 x 10-3) were near zero. The PRNP locus accounts for about 0.5, 1.5, and 0.4% of total genetic (PRNP and polygenic) variance in milk, fat, and protein yield. These values indicated that the PRNP effect is not relevant regarding genetic additive contribution. For breeding purposes, it is unlikely that selection for scrapie resistance will have an effect on the milk traits studied in the Latxa breed. Key words: association analysis, milk trait, PRNP gene, sheep [ABSTRACT FROM AUTHOR]

The aim of this study was to identify the PRNP polymorphisms outside the standard codons 136, 154 and 171 in 1110 sheep with no clinical sign of scrapie from all 18 Turkish native sheep breeds and compare our results with published data on ovine PRNP polymorphism from other regions of the world. Among the 22 amino acid polymorphisms and three silent mutations, 10 were novel for ovine PRNP: p. Gly94 Gly, p. Leu128Ile, p. Met132 Leu, p. Ser135 Arg, p. Met137 Val, p. Asn146 Lys, p. Arg159 Arg, p. Tyr160 Asn, p. Gln163 His and p. Thr193 Ser. These data reveal that sheep breeds close to the historic center of small ruminant domestication have remained highly diverse in the prion gene locus, with distinctive genetic similarities to both Asian and European sheep breeds. [ABSTRACT FROM AUTHOR]

Abstract: Scrapie, a fatal transmissible spongiform encephalopathy (TSE), occurs in two phenotypes; classical and atypical. The aim of this study was to assess the genetic risk and identify the PRNP polymorphisms for atypical scrapie in a total of 1110 healthy sheep from 18 Turkish native sheep breeds. There were 10 alleles and 23 genotypes observed based on codons 136, 141, 154 and 171 of PRNP gene. The ALRQ allele was predominant for all breeds. The AFRQ allele, associated with the susceptibility to atypical scrapie, was detected in only İvesi. The other susceptible allele, ALHQ, was found at low frequencies in Akkaraman, Kangal Akkaraman, Güneykaraman, Kıvırcık, Sakız, Dağlıç and Gökçeada breeds. Generally, the ALRQ/ALRQ genotype, which is resistant to atypical scrapie, was predominant in all breeds. Among the most susceptible genotypes to atypical scrapie, only ALHQ/ALHQ was found in this study. In addition, the ARR/ARR genotype, which has been reported in lots of atypical scrapie positive sheep from various countries, was detected in almost all Turkish native sheep breeds. According to our results, it is propounded that the susceptibility to atypical scrapie increased from eastern to western part of Turkey. Although it seems that Turkish native sheep breeds are safe from atypical scrapie, the occurrence of susceptible genotypes should be taken into consideration. [Copyright &y& Elsevier]

Prion protein (PrP) is a membrane glycoprotein whose abnormal form is believed to cause a group of disorders known as transmissible spongiform encephalopathies (TSEs), which affect the brain and nervous system of both human beings and animals. The most familiar TSEs are Creutzfeldt-Jakob Disease (CJD) in human beings, and bovine spongiform encephalopathy (BSE) and scrapie in sheep and goats. It is well established that resistance or susceptibility to scrapie has a genetic background that is closely linked to amino acid variations within PrP at positions 136 (A/V), 154 (R/H) and 171 (Q/R). The ARR (alanine at codon 136 and arginine at codons 154 and 171) allele is associated with the highest resistance to scrapie, whereas the VRQ allele is linked to the highest susceptibility. In the present study the allelic and genotypic frequencies of the PRNP gene in the Rough-coated Pomeranian Landrace (RPL) were determined. Polymorphisms at codons 136, 154 and 171 were identified with the PCR-RFLP method. Of the eight observed genotypes, ARR/ARQ (35.9%) and ARQ/ARQ (24.4%) were the most frequent. This study reported a presence of AHQ/AHR genotype (2.6%) that has not previously been recorded in any sheep breed. The predominance of wild-type ARQ (46.8%) haplotype, which is linked to the risk of scrapie development, suggested a genetic susceptibility to scrapie in RPL sheep. Although the frequency of ARR/ARR in RPL sheep was low, the highest frequency of the ARR/ARQ genotype could be helpful in increasing the number of individuals carrying the ARR/ARR genotype and reducing the risk of genetic defects within the population. [ABSTRACT FROM AUTHOR]

Allele and haplotype segregation at the polymorphic sites within the promoter (23indel) and intron 1 (12indel) regions of the PRNP gene was analyzed in Polish Holstein-Friesian cattle. More 23del/del homozygotes and fewer 23ins/ins homozygotes than expected were observed in the offspring of ♂ 23ins/del × ♀ 23ins/del parents. In the offspring of ♂ 23ins/del × ♀ 23del/del parents and ♂ 23del/del × ♀ 23ins/del parents, a trend toward more 23del/del animals and fewer 23ins/del animals than expected was noted. At the 12indel polymorphic site, the only trend found was one toward fewer 12ins/ins genotypes and more 12ins/del and 12del/del genotypes than expected in the offspring of ♂ 12ins/del × ♀ 12ins/del parents. An analysis of haplotype segregation revealed more 23del-12del/23del-12del diplotypes and fewer 23ins-12ins/23ins-12ins diplotypes at the significance threshold than expected in the offspring of ♂ 23ins-12ins/23del-12del × ♀ 23ins-12ins/23del-12del parents. [ABSTRACT FROM AUTHOR]

M. W. Head and J. W. Ironside (2012) Neuropathology and Applied Neurobiology 38, 296-310 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. [ABSTRACT FROM AUTHOR]