Mutations In Prion Protein Gene Research Articles

Pathogenic Mechanisms of the Prion Protein Gene Mutations: A Review and Speculative Hypotheses for Pathogenic Potential of the Pro39Leu Mutation in the Associated FTD-Like Phenotype

Recently, a novel, missense Pro39Leu mutation, to date unique in the N-terminal domain of the prion protein (PrP), has been reported in three patients affected by frontotemporal lobar degeneration (FTLD) syndrome, in the absence of mutations in genes known to cause dementia. Dominantly inherited mutations in the PRNP, the gene encoding PrP, have been associated with neurodegenerative disorders including Creutzfeldt-Jacob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and Fatal Familial Insomnia (FFI), but, in some cases, PRNP mutations have been found in clinical pictures resembling other neurodegenerative diseases, such as frontotemporal dementia. The prevailing view of pathogenesis posits that these point mutations are located in the C-terminal region of the PRNP gene, and, to date, the potential importance of the N-terminal domain has largely been overlooked. The purpose of this report is to review the pathogenic mechanisms of PRNP mutations by comparing the C- and N-terminal domains. Successively, we hypothesize, based on published data and albeit speculative, that the pathogenicity of the PRNP Pro39Leu mutation in determining a particular phenotype may be due to its location in the N-terminal domain. We hope that our review may awakened a surge of interest in investigate the appearance of this particular P39L-related phenotype and possible interaction between PrP and tubulin, by future functional and neuropathological studies.

Hereditary Human Prion Diseases: an Update.

Prion diseases in humans are neurodegenerative diseases which are caused by an accumulation of abnormal, misfolded cellular prion protein known as scrapie prion protein (PrPSc). Genetic, acquired, or spontaneous (sporadic) forms are known. Pathogenic mutations in the human prion protein gene (PRNP) have been identified in 10-15% of CJD patients. These mutations may be single point mutations, STOP codon mutations, or insertions or deletions of octa-peptide repeats. Some non-coding mutations and new mutations in the PrP gene have been identified without clear evidence for their pathogenic significance. In the present review, we provide an updated overview of PRNP mutations, which have been documented in the literature until now, describe the change in the DNA, the family history, the pathogenicity, and the number of described cases, which has not been published in this complexity before. We also provide a description of each genetic prion disease type, present characteristic histopathological features, and the PrPSc isoform expression pattern of various familial/genetic prion diseases.

Genetic and Pathological Follow-Up Study of Goats Experimentally and Naturally Exposed to a Sheep Scrapie Isolate.

Thirty-seven goats carrying different prion protein genotypes (PRNP) were orally infected with a classical scrapie brain homogenate from wild-type (ARQ/ARQ) sheep and then mated to obtain 2 additional generations of offspring, which were kept in the same environment and allowed to be naturally exposed to scrapie. Occurrence of clinical or subclinical scrapie was observed in the experimentally infected goats (F0) and in only one (F1b) of the naturally exposed offspring groups. In both groups (F0 and F1b), goats carrying the R154H, H154H, R211Q, and P168Q-P240P dimorphisms died of scrapie after a longer incubation period than wild-type, G37V, Q168Q-P240P, and S240P goats. In contrast, D145D and Q222K goats were resistant to infection. The immunobiochemical signature of the scrapie isolate and its pathological aspects observed in the sheep donors were substantially maintained over 2 goat generations, i.e., after experimental and natural transmission. This demonstrates that the prion protein gene sequence, which is shared by sheep and goats, is more powerful than any possible but unknown species-related factors in determining scrapie phenotypes. With regard to genetics, our study confirms that the K222 mutation protects goats even against ovine scrapie isolates, and for the first time, a possible association of D145 mutation with scrapie resistance is shown. In addition, it is possible that the sole diverse frequencies of these genetic variants might, at least in part, shape the prevalence of scrapie among naturally exposed progenies in affected herds. This study was aimed at investigating the genetic and pathological features characterizing sheep-to-goat transmission of scrapie. We show that in goats with different prion protein gene mutations, the K222 genetic variant is associated with scrapie resistance after natural and experimental exposure to ovine prion infectivity. In addition, we observed for the first time a protective effect of the D145 goat variant against scrapie. Importantly, our results demonstrate that the phenotypic characteristic of the wild-type sheep scrapie isolate is substantially preserved in goats carrying different susceptible PRNP gene variants, thus indicating that the prion protein gene sequence, which is shared by sheep and goats, plays a fundamental role in determining scrapie phenotypes.

Transmission Properties of Human PrP 102L Prions Challenge the Relevance of Mouse Models of GSS.

Inherited prion disease (IPD) is caused by autosomal-dominant pathogenic mutations in the human prion protein (PrP) gene (PRNP). A proline to leucine substitution at PrP residue 102 (P102L) is classically associated with Gerstmann-Sträussler-Scheinker (GSS) disease but shows marked clinical and neuropathological variability within kindreds that may be caused by variable propagation of distinct prion strains generated from either PrP 102L or wild type PrP. To-date the transmission properties of prions propagated in P102L patients remain ill-defined. Multiple mouse models of GSS have focused on mutating the corresponding residue of murine PrP (P101L), however murine PrP 101L, a novel PrP primary structure, may not have the repertoire of pathogenic prion conformations necessary to accurately model the human disease. Here we describe the transmission properties of prions generated in human PrP 102L expressing transgenic mice that were generated after primary challenge with ex vivo human GSS P102L or classical CJD prions. We show that distinct strains of prions were generated in these mice dependent upon source of the inoculum (either GSS P102L or CJD brain) and have designated these GSS-102L and CJD-102L prions, respectively. GSS-102L prions have transmission properties distinct from all prion strains seen in sporadic and acquired human prion disease. Significantly, GSS-102L prions appear incapable of transmitting disease to conventional mice expressing wild type mouse PrP, which contrasts strikingly with the reported transmission properties of prions generated in GSS P102L-challenged mice expressing mouse PrP 101L. We conclude that future transgenic modeling of IPDs should focus exclusively on expression of mutant human PrP, as other approaches may generate novel experimental prion strains that are unrelated to human disease.

Novel N-terminal domain mutation in prion protein detected in 2 patients diagnosed with frontotemporal lobar degeneration syndrome

Prion protein gene mutations have been associated with clinical pictures mimicking neurodegenerative diseases different from inherited prion diseases (IPD). We report a novel missense P39L mutation in the N-terminal domain of prion protein in 2 patients affected by frontotemporal lobar degeneration syndrome, negative for mutations in genes causative of dementia. Neither the first carrier, a 67-year-old male in which the onset was a progressive non-fluent aphasia, nor the second carrier, a 78-year-old male affected by frontotemporal dementia and parkinsonism, showed any clinical or instrumental findings suggestive of IPD. Genetic screening of healthy controls and in silico analysis provide support for the potential pathogenicity of this variant. Patient phenotypes, unclassifiable as prion disease, may depend on the location of the mutation in the N-terminal domain, outside the amyloid core of pathologic prion protein, although further functional studies are required to determine whether and how this mutation exerts its pathogenic effect. However, genetic screening of prion protein gene becomes relevant in familial degenerative dementia, particularly in geographical areas with high IPD prevalence.

NMR Structural Studies of Human Cellular Prion Proteins

Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative disorders associated with the conformational conversion of the cellular prion protein, PrP(C), into a pathological form known as prion or PrP(Sc). They can be classified into sporadic, inherited and infectious forms. Spontaneous generation of PrP(Sc) in inherited forms of prion diseases is caused by mutations in the human prion protein gene (PRNP). A major goal in prion biology is unraveling the molecular mechanism by which PrP(C) misfolds and leads to development of diseases. Structural characterization of various human PrP (HuPrP) variants may be helpful for better understanding of the earliest stages of the conformational changes leading to spontaneous generation of prions. Here, we review the results of the recent high-resolution nuclear magnetic resonance (NMR) structural studies on HuPrPs with pathological Q212P and V210I mutations linked with Gerstmann-Sträussler-Scheinker (GSS) syndrome and familial Creutzfeldt-Jakob disease (fCJD), respectively, and HuPrP carrying naturally occurring E219K polymorphism considered to protect against sporadic CJD (sCJD). We describe subtle local differences between the three-dimensional (3D) structures of HuPrP mutants and the wild-type (WT) protein, providing new insights into the possible key structural determinants underlying conversion of PrP(C) into PrP(Sc). Also highlighted are the most recent findings from NMR studies about the effect of pH on the structural features of HuPrP with V210I mutation.

Inherited prion disease A117V is not simply a proteinopathy but produces prions transmissible to transgenic mice expressing homologous prion protein.

Prions are infectious agents causing fatal neurodegenerative diseases of humans and animals. In humans, these have sporadic, acquired and inherited aetiologies. The inherited prion diseases are caused by one of over 30 coding mutations in the human prion protein (PrP) gene (PRNP) and many of these generate infectious prions as evidenced by their experimental transmissibility by inoculation to laboratory animals. However, some, and in particular an extensively studied type of Gerstmann-Sträussler-Scheinker syndrome (GSS) caused by a PRNP A117V mutation, are thought not to generate infectious prions and instead constitute prion proteinopathies with a quite distinct pathogenetic mechanism. Multiple attempts to transmit A117V GSS have been unsuccessful and typical protease-resistant PrP (PrPSc), pathognomonic of prion disease, is not detected in brain. Pathogenesis is instead attributed to production of an aberrant topological form of PrP, C-terminal transmembrane PrP (CtmPrP). Barriers to transmission of prion strains from one species to another appear to relate to structural compatibility of PrP in host and inoculum and we have therefore produced transgenic mice expressing human 117V PrP. We found that brain tissue from GSS A117V patients did transmit disease to these mice and both the neuropathological features of prion disease and presence of PrPSc was demonstrated in the brains of recipient transgenic mice. This PrPSc rapidly degraded during laboratory analysis, suggesting that the difficulty in its detection in patients with GSS A117V could relate to post-mortem proteolysis. We conclude that GSS A117V is indeed a prion disease although the relative contributions of CtmPrP and prion propagation in neurodegeneration and their pathogenetic interaction remains to be established.

Novel prion protein gene mutation at codon 196 (E196A) in a septuagenarian with Creutzfeldt–/INS;Jakob disease

Creutzfeldt–/INS;Jakob disease (CJD) is a rare and rapidly progressive neurodegenerative disease in the central nervous system, which may occur in inherited, acquired (variant and iatrogenic), or spontaneous (sporadic) forms. Genetic CJD is caused by a point mutation of the prion protein (PrP) gene (PRNP) on human chromosome 20. Here we report a 76-year-old CJD patient found unexpectedly to harbor a novel mutation in PRNP. Routine clinical investigations were undertaken to elucidate the cause of the rapidly progressive dementia and neurological decline manifested by the patient.

Facilitative effects of ginkgolide B and velvet antler polypeptide on cholinergic progenitor differentiation

WCN 2013 No: 74 Topic: 5 — Dementia Novel prion protein gene mutation at codon 196 (E196A) in a septuagenarian with Creutzfeldt–Jakob disease H. Zhang, M. Wang, L. Sun. Department of Neurology, The First Bethune Hospital of Jilin University, Changchun, China; Department of Neurology, Tengzhou Central People's Hospital, Tengzhou, China Creutzfeldt–Jakob disease (CJD) is a rare and rapidly progressive neurodegenerative disease in the central nervous system, which may occur in inherited, acquired (variant and iatrogenic), or spontaneous (sporadic) forms. Genetic CJD is caused by a point mutation of the prion protein (PrP) gene (PRNP) on human chromosome 20. Here we report a 76-year-old CJD patient found unexpectedly to harbor a novel mutation in PRNP. Routine clinical investigations were undertaken to elucidate the cause of the rapidly progressive dementia and neurological decline manifested by the patient. Both neuron-specific enolase (NSE) and 14-3-3 protein in the cerebrospinal fluid (CSF) were positive. Magnetic resonance imaging (MRI) diffusion-weighted image (DWI) revealed ribbon-like high signals in the bilateral frontal, insular, occipital and parietal cortices, suggestive of CJD. Electroencephalography showed typical periodic synchronous discharge (PSD). Continuous deterioration of clinical symptoms was observed, and typical manifestations including myoclonus and akinetic mutism gradually appeared. CJD was clinically diagnosed based on the above characteristic findings. Interestingly, a point mutation of PRNP at codon 196 (E196A) was detected. To our knowledge, we are the first to report the point mutation of PRNP at codon 196 (E196A) in patients with CJD. doi:10.1016/j.jns.2013.07.1118 Abstract — WCN 2013 No: 75 Topic: 5 — Dementia Facilitative effects of ginkgolide B and velvet antler polypeptide on cholinergic progenitor differentiation WCN 2013 No: 75 Topic: 5 — Dementia Facilitative effects of ginkgolide B and velvet antler polypeptide on cholinergic progenitor differentiation H. Zhang, X. Sun, L. Sun. Department of Neurology, The First Bethune Hospital of Jilin University, Changchun, China; Department of Neurology, People's Hospital of Zhengzhou, Zhengzhou, China Objective: We aim to investigate the effects of ginkgolide B (GKB) and velvet antler polypeptide (VAP) on the generation and differentiation of cholinergic progenitors. Methods: Telencephalon cells were cultured. GKB, VAP and the combination of them were added into the culture medium. Cell culture was terminated on day 4, and then the SP kit (Boster, China) was used to mark the ChAT and BrdU positive cells. The data of these positive cells were analyzed among groups. Results: Compared to the control group, the neurospheres of experimental group were bigger and the neurites were longer and stronger. More cells migrated from neurospheres. Most cells of ChaT positive distributed on the edge of neurospheres; only a small amount scattered among the neurospheres. The number of ChaT positive neurons in experimental group was higher than that in the control group, especially the GKB and VAP combined group. The VAP group had the most BrdU positive cells. Conclusion: GKB and VAP, especially when used together, could facilitate the generation and differentiation of cholinergic progenitors efficiently. doi:10.1016/j.jns.2013.07.1119 Abstract — WCN 2013 No: 9 Topic: 5 — Dementia Antidepressant treatment improves estrogen levels and cognitive function in postmenopausal anxiety/depression patients WCN 2013 No: 9 Topic: 5 — Dementia Antidepressant treatment improves estrogen levels and cognitive function in postmenopausal anxiety/depression patients B.R. Zhou. GuangZhou Medical College, GuangZhou, China Rationale and objectives: The current study investigated the role of antidepressant treatment on the level of sex hormones and cognitive function in post-menopausal anxiety/depression patients. Methods: A total of 82 post-menopausal patients who were diagnosed with anxiety/depression disorder and were not receiving hormonal replacement therapy participated in a prospective, 6-month, open-label naturalistic study. Patients were divided into an antidepressant treatment group (44 cases) and a non-antidepressant treatment (control) group (38 cases). We collected demographic data and tested sex hormone levels and assessed the extent of psychological disorder and examined cognitive function. Results: 1) The E2 level at six-months post-treatment was significantly increased, conversely, FSH and LH levels were significantly decreased, in the antidepressant treatment group compared with pre-therapy or the control group (P b 0.01). 2) HARS-14 and CHDS scores decreased significantly more, MoCA scores significantly improved in the antidepressant treatment group than in the pre-therapy or the control group (P b 0.01). 3) E2 levels were strongly correlated with MoCA and CHDS or HARDS-14 scores at preand post-therapy in the antidepressant treatment group. E2 levels maintained a significant association with improvement in CHDS at post-therapy, even we controlled for age, severity of depression, and MoCA scores, (R 0.35, P 0.038). Conclusions: The antidepressant Paroxetine improved cognitive function in postmenopausal anxiety–depression patients, possibly by increasing endogenous estrogen discharge or delaying degeneration of the gonads. doi:10.1016/j.jns.2013.07.1120 Abstracts / Journal of the Neurological Sciences 333 (2013) e292–e357 e297

Prion diseases and sleep disorders

Prion diseases (PrD) are a group of encephalopathies with neurodegenerative changes caused by prion protein (PrP) whose characteristic datum is transmissibility. In most cases they occur in a sporadic form although a group of them are familial associated with mutations in PrP gene. Phenotypic variability of fatal familial insomnia (FFI) versus familial Creutzfeldt-Jakob disease178 (fCJD178) seems to determine the different methionine⁃valine polymorphism at codon 129 of the PrP gene. Sleep disorders is one of the important clinical features for the diagnosis and definition of PrD. FFI, a hereditary disorder characterized by loss of physiological sleep with oneiric stupor, autonomic and motor hyperactivity. The polysomnography (PSG) shows disappearance of the physiological pattern of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, as well as sleep spindles and K-complexes were absent. The hypothesis of the origin of these disorders is thalamic neuronal loss, especially in the anterior and dorsomedial nuclei, described in the neuropathology of these patients; besides, PET reveals hypofunction of thalamic nuclei, centres responsible for controlling wake-sleep. In CJD the wake-sleep disorders is not considered characteristic; nonetheless, frequent alterations have been found in the electroencephalographic registers of sleep. Besides thalamic neurodegeneration, there could be common etiopathogenic mechanisms in PrD in relation to the biological function of PrP.

Novel prion protein gene mutation at codon 196 (E196A) in a septuagenarian with Creutzfeldt–Jakob disease

Creutzfeldt–Jakob disease (CJD) is a rare and rapidly progressive neurodegenerative disease of the central nervous system, which may occur in inherited, acquired (variant and iatrogenic), or spontaneous (sporadic) forms. We report a 76-year-old Chinese man with CJD found to have a novel mutation in the prion protein gene (PRNP). The 14-3-3 protein was positive in the cerebrospinal fluid; diffusion-weighted MRI revealed ribbon-like high signal intensity in the bilateral cortices; and electroencephalography showed typical periodic synchronous discharge. CJD was diagnosed based on characteristic clinical manifestations. Interestingly, a point mutation of PRNP at codon 196 (E196A: GAG→GCG) was detected. In conclusion, we identified a patient with CJD with a novel PRNP mutation, which expands the spectrum of PRNP mutations in CJD.

Relationships between clinicopathological features and cerebrospinal fluid biomarkers in Japanese patients with genetic prion diseases.

A national system for surveillance of prion diseases (PrDs) was established in Japan in April 1999. Here, we analyzed the relationships among prion protein gene (PRNP) mutations and the clinical features, cerebrospinal fluid (CSF) markers, and pathological characteristics of the major genotypes of genetic PrDs (gPrDs). We retrospectively analyzed age at onset and disease duration; the concentrations and incidences of 14-3-3 protein, tau protein, and abnormal prion protein (PrPSc) in the CSF of 309 gPrD patients with P102L, P105L, E200K, V180I, or M232R mutations; and brain pathology in 32 autopsied patients. Three clinical phenotypes were seen: rapidly progressive Creutzfeldt-Jakob disease (CJD), which included 100% of E200K cases, 70% of M232R, and 21% of P102L; slowly progressive CJD, which included 100% of V180I and 30% of M232R; and Gerstmann-Sträussler-Scheinker disease, which included 100% of P105L and 79% of P102L. PrPSc was detected in the CSF of more than 80% of patients with E200K, M232R, or P102L mutations but in only 39% of patients with V180I. V180I was accompanied by weak PrP immunoreactivity in the brain. Patients negative for PrPSc in the CSF were older at disease onset than positive patients. Patients with mutations associated with high 14-3-3 protein levels in the CSF typically had synaptic deposition of PrP in the brain and a rapid course of disease. The presence of small PrP protein fragments in brain homogenates was not correlated with other clinicopathological features. Positivity for PrPSc in the CSF may reflect the pathological process before or at disease onset, or abnormality in the secretion or metabolism of PrPSc. The amount of 14-3-3 protein in the CSF likely indicates the severity of the pathological process and accompanying neuronal damage. These characteristic features of the CSF in cases of gPrD will likely facilitate accurate diagnosis and clinicopathological study of the various disease subtypes.

Systematic investigation of predicted effect of nonsynonymous SNPs in human prion protein gene: a molecular modeling and molecular dynamics study

Nonsynonymous mutations in the human prion protein (HuPrP) gene contribute to the conversion of HuPrPC to HuPrPSc and amyloid formation which in turn leads to prion diseases such as familial Creutzfeldt–Jakob disease and Gerstmann–Straussler–Scheinker disease. In order to better understand and predict the role of HuPrP mutations, we developed the following procedure: first, we consulted the Human Genome Variation database and dbSNP databases, and we reviewed literature for the retrieval of aggregation-related nsSNPs of the HuPrP gene. Next, we used three different methods – Polymorphism Phenotyping (PolyPhen), PANTHER, and Auto-Mute – to predict the effect of nsSNPs on the phenotype. We compared the predictions against experimentally reported effects of these nsSNPs to evaluate the accuracy of the three methods: PolyPhen predicted 17 out of 22 nsSNPs as “probably damaging” or “possibly damaging”; PANTHER predicted 8 out of 22 nsSNPs as “Deleterious”; and Auto-Mute predicted 9 out of 20 nsSNPs as “Disease”. Finally, structural analyses of the native protein against mutated models were investigated using molecular modeling and molecular dynamics (MD) simulation methods. In addition to comparing predictor methods, our results show the applicability of our procedure for the prediction of damaging nsSNPs. Our study also elucidates the obvious relationship between predicted values of aggregation-related nsSNPs in HuPrP gene and molecular modeling and MD simulations results. In conclusion, this procedure would enable researchers to select outstanding candidates for extensive MD simulations in order to decipher more details of HuPrP aggregation.An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:34

プリオン病の臨床像と疫学，とくに硬膜移植後CJD

In Japan, prion diseases are classified into 76.6％ with sporadic Creutzfeldt-Jakob disease (sCJD), 19.6％ with genetic prion diseases, and 4.9％ with acquired prion disease. In sCJD, MM1 type sCJD, which show typical clinical course of CJD, is the most common. Among atypical sCJD cases, MM2 type sCJD is the most common. In genetic prion diseases, the most common mutation of prion protein gene is V180I. All cases with acquired prion diseases except for one case of variant CJD are dura mater graft-associated CJD (dCJD), and the number of dCJD in Japan is account for more than 60％ of all patients with dCJD all over the world. The remarkable frequency of dura mater graft use in Japan might contribute to the elevated incidence of dCJD, but the possible reasons for the disproportionate use of this procedure in Japan remain unclear. Our recent study revealed that differences in the medical conditions precipitating dura mater graft might contribute to the frequent use of cadaveric dura mater and the higher incidence of dCJD in Japan.

022 Voxelwise analysis of cerebral diffusion tensor imaging in prion diseases

The need to find a prion disease neuroimaging biomarker is important with the development of therapeutic agents. Diffusion tensor imaging (DTI) is an MRI sequence that can visualise white matter...

Sporadic fatal insomnia in a young woman: A diagnostic challenge: Case Report

BackgroundSporadic fatal insomnia (sFI) and fatal familial insomnia (FFI) are rare human prion diseases.Case PresentationWe report a case of a 33-year-old female who died of a prion disease for whom the diagnosis of sFI or FFI was not considered clinically. Following death of this patient, an interview with a close family member indicated the patient's illness included a major change in her sleep pattern, corroborating the reported autopsy diagnosis of sFI. Genetic tests identified no prion protein (PrP) gene mutation, but neuropathological examination and molecular study showed protease-resistant PrP (PrPres) in several brain regions and severe atrophy of the anterior-ventral and medial-dorsal thalamic nuclei similar to that described in FFI.ConclusionsIn patients with suspected prion disease, a characteristic change in sleep pattern can be an important clinical clue for identifying sFI or FFI; polysomnography (PSG), genetic analysis, and nuclear imaging may aid in diagnosis.

Prevalent Mutations of Human Prion Protein: A Molecular Modeling and Molecular Dynamics Study

Point mutations in the human prion protein gene, leading to amino acid substitutions in the human prion protein contribute to conversion of PrPC to PrPSc and amyloid formation, resulting in prion diseases such as familial Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSS), and fatal familial insomnia. We have investigated impressions of prevalent mutations including Q217R, D202N, F198S, on the human prion protein and compared the mutant models with wild types. Structural analyses of models were performed with molecular modeling and molecular dynamics simulation methods. According to our results, frequently occurred mutations are observed in conserved and fully conserved sequences of human prion protein and the most fluctuation values occur in the Helix 1 around residues 144–152 and C-terminal end of the Helix 2. Our analysis of results obtained from MD simulation clearly shows that this long-range effect plays an important role in the conformational fluctuations in mutant structures of human prion protein. Results obtained from molecular modeling such as creation or elimination of some hydrogen bonds, increase or decrease of the accessible surface area and molecular surface, loss or accumulation of negative or positive charges on specific positions, and altering the polarity and pKa values, show that amino acid point mutations, though not urgently change the stability of PrP, might have some local impacts on the protein interactions which are required for oligomerization into fibrillar species.

Experience With Preventive Genetic Testing of Corneal Donors in Slovakia

The purpose of this study was (1) to detect asymptomatic carriers of the prion protein gene mutation E200K, which is associated with Creutzfeldt-Jakob disease (CJD), in corneal donors and in the general population of Slovakia and (2) to assess the genetic testing of corneal donors as an effective preventive measure against iatrogenic infection in a country with an unusually high incidence of genetic CJD. The prion protein gene (PRNP) was analyzed in 1133 corneal donors and 970 control subjects to search for E200K mutation and to determine the genotype at codon 129. Mutation E200K was found in 2 of the 1133 donors and in 4 of the 970 control subjects. The most frequent genotype at the codon 129 polymorphic region was methionine homozygous (48% of donors and controls). An E200K mutation, which confers a risk of developing genetic CJD, was detected in corneal donors and in the general population. The majority of subjects were codon 129 methionine homozygous that increases susceptibility to CJD. Genetic testing of corneal donors in Slovakia is a useful and effective preventive measure against iatrogenic CJD through human corneal transplantation in the investigated population.

PSEN1 and PRNP Gene Mutations Co-occurrence Makes Onset Very Early in a Family with FTD Phenotype

Prion protein (PRNP) gene mutations have recently been associated with clinical pictures resembling Frontotemporal dementia (FTD). We describe a novel seven extra-repeat insertional mutation in the PRNP gene in a family affected by early-onset autosomal dominant FTD previously reported as caused by a PSEN1 mutation in which there was inconsistency between clinical picture and genotype. Both mutations were pathogenic and showed a variable penetrance when present separately; when occurring together, the onset was very early, within the third decade of life. Genetic screening of the PRNP gene becomes of major importance in early onset autosomal dominant dementia.

Gerstmann-Sträussler-Scheinker disease due to a novel prion protein gene mutation

Prion diseases are rapidly progressive, fatal brain disorders arising sporadically, genetically, or by infection.1 Dominant, high-penetrance mutations in the gene ( PRNP ) encoding the prion protein (PrP) cause 5%–15% of human cases.2 Gerstmann-Straussler-Scheinker (GSS) disease is an exceedingly rare inherited phenotype,2 defined neuropathologically by multicentric, PrP-containing amyloid plaques. We present a patient with prominent seizures, cognitive decline, and ataxia who was found to have a novel mutation in PRNP . ### Case report. A 34-year-old man presented in status epilepticus. Despite multiple anticonvulsants, he continued to have complex partial and generalized tonic-clonic seizures. He developed an unsteady gait, slurred speech, and personality change marked by disinhibition. Three years prior, he had onset of gradual cognitive decline, which accelerated following the onset of epilepsy. Eight years prior, the patient had developed night terrors, which resolved spontaneously after 6 years. Otherwise, the patient was healthy. His 7-year-old son was recently diagnosed with Asperger syndrome. Examination showed a Montreal Cognitive Assessment score of 15/30. Neuropsychiatric assessment revealed memory and executive function deficits. The patient demonstrated saccadic pursuit, square wave jerks, and flaccid dysarthria. Power and reflexes were normal; plantar responses were flexor. There was diffuse paratonia and axial rigidity. Finger-to-nose testing was normal but he had mild difficulty with heel-to-shin testing. Rapid alternating movements were impaired by apraxia. Gait was slightly wide-based. Nonstimulus-sensitive myoclonus was present. The patient underwent extensive investigations (table e-1 on the Neurology ® Web site at www.neurology.org). Brain MRI on multiple occasions showed mild diffuse cortical atrophy and mild cerebellar vermian atrophy without restricted diffusion or gadolinium …