20 results on '"Claudia Ponto"'
Search Results
2. A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk.
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Pascual Sanchez-Juan, Matthew T Bishop, Gabor G Kovacs, Miguel Calero, Yurii S Aulchenko, Anna Ladogana, Alison Boyd, Victoria Lewis, Claudia Ponto, Olga Calero, Anna Poleggi, Ángel Carracedo, Sven J van der Lee, Thomas Ströbel, Fernando Rivadeneira, Albert Hofman, Stéphane Haïk, Onofre Combarros, José Berciano, Andre G Uitterlinden, Steven J Collins, Herbert Budka, Jean-Philippe Brandel, Jean Louis Laplanche, Maurizio Pocchiari, Inga Zerr, Richard S G Knight, Robert G Will, and Cornelia M van Duijn more...
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Medicine ,Science - Abstract
We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62x10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Genomes Project and imputed genotypes from the Rotterdam Study (Total n=12967). The meta-analysis of the results showed that rs6107516 (p-value=3.00x10-8) and rs6951643 (p-value=3.91x10-5) remained as the two most significantly associated SNPs. Rs6951643 is located in an intronic region of GRM8, a gene that was additionally tagged by a cluster of 12 SNPs within our top100 ranked results. GRM8 encodes for mGluR8, a protein which belongs to the metabotropic glutamate receptor family, recently shown to be involved in the transduction of cellular signals triggered by the prion protein. Pathway enrichment analyses performed with both Ingenuity Pathway Analysis and ALIGATOR postulates glutamate receptor signalling as one of the main pathways associated with sCJD. In summary, we have detected GRM8 as a novel, non-PRNP, genome-wide significant marker associated with heightened disease risk, providing additional evidence supporting a role of glutamate receptors in sCJD pathogenesis. more...
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- 2014
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3. Investigating the association of ApoE genotypes with blood-brain barrier dysfunction measured by cerebrospinal fluid-serum albumin ratio in a cohort of patients with different types of dementia.
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André Karch, Henrike Manthey, Claudia Ponto, Peter Hermann, Uta Heinemann, Christian Schmidt, and Inga Zerr
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Medicine ,Science - Abstract
BACKGROUND: Since more than a decade ApoE is known to be a strong risk factor for Alzheimer's disease (AD); however, molecular pathways mediating this risk are still unclear. In recent years it has been hypothesized that ApoE might play a role in the disintegration of blood-brain barrier (BBB). In the present study we addressed the question if ApoE genotypes might be associated with BBB function measured by albumin ratio (QAlb) in a large cohort of patients with different types of dementia. METHODS: Five hundred twenty (520) patients with Creutzfeldt-Jakob disease (CJD, n = 350), Alzheimer's disease (n = 71) and cerebral small vessel disease (n = 99) were assessed for their ApoE genotype. BBB function was measured in all patients using QAlb and was compared between ApoE genotypes. Dominant and additive genetic models were assumed in order to investigate the potential effect of ApoE on BBB function. RESULTS: We observed no systematic differences in QAlb between ApoE genotypes within the present study. Increased QAlb levels were shown for those without E3 allele in the subgroup of CJD patients when assuming a dominant genetic model (p = 0.035). This could not be confirmed for patients with other forms of dementia (p = 0.234). DISCUSSION: Although there was some evidence for a protective effect of E3 alleles in CJD patients, this study does not support the hypothesis of a systematic role of ApoE genotypes in BBB function in individuals with a diagnosis of dementia. Thus, changes in BBB function do not seem to contribute to the increased risk of cognitive decline associated with certain ApoE genotypes. The interpretation of the results of this study must take into account that BBB function was only assessed by measuring QAlb which has been shown to be a good marker for overall BBB integrity but might not reflect all qualities of the barrier. more...
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- 2013
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4. Age at onset in genetic prion disease and the design of preventive clinical trials
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Michael D. Geschwind, Christiane Stehmann, Janna Kenny, Sabina Capellari, Ryusuke Ae, Sonia M Vallabh, Leonel T. Takada, Masahito Yamada, Piero Parchi, Tadashi Tsukamoto, Steven J. Collins, Jamie Fong, Nobuo Sanjo, Claudia Ponto, Jean Louis Laplanche, Inga Zerr, Tobias Knipper, Jean Philippe Brandel, Margaret C. Orseth, Peter Hermann, Yosikazu Nakamura, Simon Mead, Stéphane Haïk, Miguel Calero, Tetsuyuki Kitamoto, Tsuyoshi Hamaguchi, Jesús de Pedro-Cuesta, Ignazio Roiter, Roberto Chiesa, Eric Vallabh Minikel, Jiri G. Safar, Hidehiro Mizusawa, Minikel E.V., Vallabh S.M., Orseth M.C., Brandel J.-P., Haik S., Laplanche J.-L., Zerr I., Parchi P., Capellari S., Safar J., Kenny J., Fong J.C., Takada L.T., Ponto C., Hermann P., Knipper T., Stehmann C., Kitamoto T., Ae R., Hamaguchi T., Sanjo N., Tsukamoto T., Mizusawa H., Collins S.J., Chiesa R., Roiter I., de Pedro-Cuesta J., Calero M., Geschwind M.D., Yamada M., Nakamura Y., and Mead S. more...
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0301 basic medicine ,Adult ,Male ,Creutzfeldt-Jakob disease, human prions, PRNP gene, clinical trials, biomarkers, neurodegenerative diseases ,Adolescent ,Genotype ,Penetrance ,Disease ,Kaplan-Meier Estimate ,Bioinformatics ,Article ,Prion Proteins ,PRNP ,Prion Diseases ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Medicine ,Humans ,Young adult ,Age of Onset ,Child ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,Clinical Trials as Topic ,Surrogate endpoint ,Proportional hazards model ,business.industry ,Middle Aged ,3. Good health ,Clinical trial ,030104 developmental biology ,Research Design ,Mutation ,Female ,Neurology (clinical) ,Age of onset ,business ,030217 neurology & neurosurgery - Abstract
ObjectiveTo determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease.MethodsWe assembled age at onset or death data from 1,094 individuals with high penetrance mutations in the prion protein gene (PRNP) in order to generate survival and hazard curves and test for genetic modifiers of age at onset. We used formulae and simulations to estimate statistical power for clinical trials.ResultsGenetic prion disease age at onset varies over several decades for the most common mutations and neither sex, parent's age at onset, nor PRNP codon 129 genotype provided additional explanatory power to stratify trials. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials.ConclusionThe characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a postmarketing study could provide opportunities for subsequent determination of clinical benefit. more...
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- 2019
5. Doxycycline in early CJD: a double-blinded randomised phase II and observational study
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Matthias Schmitz, Inga Zerr, Walter J. Schulz-Schaeffer, Henrike Manthey, Fabian Fincke, Maren Breithaupt, Tim Friede, Anna Krasnianski, Katharina Kramer, Daniela Varges, Uta Heinemann, and Claudia Ponto more...
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Male ,0301 basic medicine ,medicine.medical_specialty ,Prions ,Phases of clinical research ,Creutzfeldt-Jakob Syndrome ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Humans ,Age of Onset ,Neurodegeneration ,Survival rate ,Aged ,Doxycycline ,business.industry ,Middle Aged ,Anti-Bacterial Agents ,3. Good health ,Surgery ,Survival Rate ,Clinical trial ,Psychiatry and Mental health ,Treatment Outcome ,030104 developmental biology ,Propensity score matching ,Cohort ,Female ,Neurology (clinical) ,Age of onset ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Objectives The main objective of the present study is to study the therapeutic efficiency of doxycycline in a double-blinded randomised phase II study in a cohort of patients with sporadic Creutzfeldt-Jakob disease (sCJD). Methods From the National Reference Center of TSE Surveillance in Germany, patients with probable or definite sCJD were recruited for a double-blinded randomised study with oral doxycycline (EudraCT 2006-003934-14). In addition, we analysed the data from patients with CJD who received compassionate treatment with doxycycline in a separate group. Potential factors which influence survival such as age at onset, gender, codon 129 polymorphism and cognitive functions were evaluated. The primary outcome measure was survival. Results Group 1: in the double-blinded randomised phase II study, 7 patients in the treatment group were compared with 5 controls. Group 2: 55 patients with sCJD treated with oral doxycycline were analysed and compared with 33 controls by a stratified propensity score applied to a Cox proportional hazard analysis. The results of both studies were combined by means of a random-effects meta-analysis. A slight increase in survival time in the doxycycline treatment group was observed (p=0.049, HR=0.63 (95% CI 0.402 to 0.999)). Conclusions On the basis of our studies, a larger trial of doxycycline should be performed in persons in the earliest stages of CJD. Trial registration number EudraCT 2006-003934-14; Results. more...
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- 2016
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6. Age of onset in genetic prion disease and the design of preventive clinical trials
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Piero Parchi, Hidehiro Mizusawa, Claudia Ponto, Nobuo Sanjo, Janna Kenny, Inga Zerr, Jean Louis Laplanche, Tobias Knipper, Miguel Calero, Jiri G. Safar, Yosikazu Nakamura, Stéphane Haïk, Simon Mead, Sabina Capellari, Leonel T. Takada, Ignazio Roiter, Christiane Stehmann, Tadashi Tsukamoto, Sonia M Vallabh, Jamie Fong, Tsuyoshi Hamaguchi, Masahito Yamada, Margaret C. Orseth, Eric Vallabh Minikel, Steven J. Collins, Michael D. Geschwind, Ryusuke Ae, Tetsuyuki Kitamoto, Jean Philippe Brandel, Peter Hermann, Roberto Chiesa, and Jesús de Pedro-Cuesta more...
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0303 health sciences ,medicine.medical_specialty ,Surrogate endpoint ,business.industry ,Disease ,3. Good health ,law.invention ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,Drug development ,Randomized controlled trial ,law ,Clinical endpoint ,medicine ,Biomarker (medicine) ,Age of onset ,Intensive care medicine ,business ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Regulatory agencies worldwide have adopted programs to facilitate drug development for diseases where the traditional approach of a randomized trial with a clinical endpoint is expected to be prohibitively lengthy or difficult. Here we provide quantitative evidence that this criterion is met for the prevention of genetic prion disease. We assemble age of onset or death data fromN=1,094 individuals with high penetrance mutations in the prion protein gene (PRNP), generate survival and hazard curves, and estimate statistical power for clinical trials. We show that, due to dramatic and unexplained variability in age of onset, randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials. Instead, the characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Biomarker-based trials may require post-marketing studies to confirm clinical benefit. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a post-marketing study could provide opportunities for subsequent determination of clinical benefit. more...
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- 2018
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7. Clinical findings and diagnosis in genetic prion diseases in Germany
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Anna Krasnianski, Inga Zerr, Kai Kallenberg, Hans A. Kretzschmar, Uta Heinemann, Daniela Varges, Jasmine Kortt, Walter J. Schulz-Schaeffer, and Claudia Ponto
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Adult ,Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Pathology ,Ataxia ,Genotype ,Prions ,Epidemiology ,DNA Mutational Analysis ,Disease ,Electroencephalography ,Creutzfeldt-Jakob Syndrome ,Prion Proteins ,White People ,Prion Diseases ,03 medical and health sciences ,0302 clinical medicine ,Germany ,Aphasia ,medicine ,Humans ,Dementia ,Genetic Predisposition to Disease ,In patient ,Codon ,Polymorphism, Genetic ,medicine.diagnostic_test ,business.industry ,Neuropsychology ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,030104 developmental biology ,Mutation ,Female ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
To describe the clinical syndrome and diagnostic tests in patients with genetic prion diseases (gPD) in Germany. Clinical features, MRI, EEG, and CSF markers were studied in 91 patients (28 D178N, 20 E200K, 17 inserts, 13 V210I, 8 P102L, 5 E196K). Dementia (35 %) and ataxia (29 %) were the most common initial symptoms and signs. A wide variety and high frequency of neurological/psychiatric symptoms and signs was found during disease course in all patients independently of the type of the mutation. Psychiatric manifestations were frequent (87 %). Neuropsychological abnormalities were observed in 67 %, and aphasia was the most common disturbance (45 %). In E200K, V210I and D178N patients, visual/oculomotor deficits were followed by ataxia early in the disease. Dementia followed by ataxia at onset was common in patients with insert and E196K mutation. P102L patients had isolated ataxia over a longer time period followed by pyramidal signs. Dementia was present only late in the disease course. All clinical routine tests such as MRI, EEG and CSF tests were less sensitive than in sporadic CJD. We provide the first detailed analysis of clinical signs and symptoms in a large group of patients with gPD. Frequency of clinical symptoms and signs was similar in different mutations in a later disease course, but the sequence of occurrence may be of great diagnostic importance. CSF markers were shown to be more sensitive than MRI and EEG. more...
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- 2015
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8. Diagnostic profiles of patients with late-onset Creutzfeldt–Jakob disease differ from those of younger Creutzfeldt–Jakob patients: a historical cohort study using data from the German National Reference Center
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André Karch, David Summers, Inga Zerr, Peter Hermann, Lena Maria Raddatz, Claudia Ponto, and Department of Neurology, National Reference Center for TSE, Clinical Dementia Center, University Medical School Göttingen, Göttingen, Germany, andre.karch@helmholtz-hzi.de. more...
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Male ,Pediatrics ,medicine.medical_specialty ,Neurology ,Databases, Factual ,Late onset ,Creutzfeldt-Jakob Syndrome ,Cohort Studies ,Germany ,Humans ,Medicine ,Dementia ,Age of Onset ,Aged ,Neuroradiology ,Aged, 80 and over ,medicine.diagnostic_test ,business.industry ,Magnetic resonance imaging ,medicine.disease ,Hyperintensity ,3. Good health ,Surgery ,Survival Rate ,Population Surveillance ,Female ,Neurology (clinical) ,Age of onset ,business ,Cohort study - Abstract
In contrast to other neurodegenerative diseases, sporadic Creutzfeldt-Jakob disease (sCJD) is rarely diagnosed in patients older than 75 years. Data describing the characteristics of sCJD in the very old are rare and inconclusive. Therefore, a historical cohort study was designed to evaluate clinical, cerebrospinal fluid (CSF), electroencephalography (EEG), and magnetic resonance imaging (MRI) features of this group. Patients older than 75 years identified via the German surveillance program from 2001 to 2012 (n = 73) were compared to a random subsample of sCJD patients younger than 75 (n = 73) from the same time period using an historical cohort design. Older patients showed a faster disease progression represented by an earlier point of diagnosis and a shorter survival time (p < 0.001). In the early stages of disease, older patients presented slightly more often with dementia (p = 0.127) or dysarthria (p = 0.238), whereas disorders of the extrapyramidal (p = 0.056) and visual system (p = 0.015) were more common in the younger group. Atypical MRI profiles such as MRI lesions restricted to one hemisphere (p < 0.001) or cortical lesions only (p = 0.258) were found more frequently in patients older than 75 years, whereas typical cortical and basal ganglia hyperintensities were more common in the younger group (p = 0.001). We demonstrated for the first time that patients with late-onset sCJD differ from younger sCJD patients with respect to MRI profiles and initial clinical presentation, but not among CSF markers. Misclassification of Creutzfeldt-Jakob disease cases in patients older than 75 years seems likely due to atypical clinical and radiological presentation. This might contribute to lower sCJD incidence rates in this age group. more...
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- 2014
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9. Detection of Infectivity in Blood of Persons with Variant and Sporadic Creutzfeldt-Jakob Disease
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Séverine Lugan, Saima Zafar, Claudia Ponto, Fabien Corbière, Caroline Lacroux, Inga Zerr, Jean-Yves Douet, Naima Aron, Armand Perret-Liaudet, Juan María Torres, Olivier Andreoletti, Hervé Cassard, Interactions hôtes-agents pathogènes [Toulouse] (IHAP), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Georg-August-University [Göttingen], Hospices Civils de Lyon (HCL), BioRan, Partenaires INRAE, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria = National Institute for Agricultural and Food Research and Technology (INIA), JPND program (DEMTEST: Biomarker based diagnosis of rapid progressive dementias-optimization of diagnostic protocols) 01ED1201A, Robert Koch-Institute through funds of the Federal Ministry of Health 1369-341, European Project: 222887,EC:FP7:KBBE,FP7-KBBE-2007-2A,PRIORITY(2009), Andreoletti, Olivier, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT), and Georg-August-University = Georg-August-Universität Göttingen more...
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Erythrocytes ,Epidemiology ,animal diseases ,lcsh:Medicine ,Disease ,Creutzfeldt-Jakob Syndrome ,Creutzfeldt-Jakob ,Mice ,infectiosite ,Leukocytes ,TSE ,spongiform encephalopathy ,transmissible spongiform encephalopathy ,Infectivity ,Transmissible spongiform encephalopathy ,infectivity ,Dispatch ,Brain ,Sporadic Creutzfeldt-Jakob disease ,3. Good health ,Mice transgenic ,CJD ,Santé publique et épidémiologie ,Infectious Diseases ,patient ,Autre (Sciences du Vivant) ,Microbiology (medical) ,[SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT] ,Prions ,creutzfeldt jacob ,Médecine humaine et pathologie ,Mice, Transgenic ,Biology ,lcsh:Infectious and parasitic diseases ,prion ,blood ,mental disorders ,sang ,medicine ,vCJD ,Animals ,Humans ,lcsh:RC109-216 ,encéphalopathie spongiforme transmissible ,lcsh:R ,medicine.disease ,Virology ,Creutzfeldt-Jakob disease ,nervous system diseases ,Disease Models, Animal ,sCJD ,Immunology ,maladie de creutzfeldt jacob ,Human health and pathology ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Cattle ,mice ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; We report the presence of infectivity in erythrocytes, leukocytes, and plasma of 1 person with variant Creutzfeldt-Jakob disease and in the plasma of 2 in 4 persons whose tests were positive for sporadic Creutzfeldt-Jakob disease. The measured infectivity levels were comparable to those reported in various animals with transmissible spongiform encephalopathies. more...
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- 2014
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10. Prionerkrankungen — welche Rolle spielen sie heute?
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Claudia Ponto and I. Zerr
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Gynecology ,medicine.medical_specialty ,Philosophy ,medicine - Abstract
Das Konzept der Protein-Fehlfaltung als Ursache einer Neurodegeneration wie der Creutzfeldt-Jakob-Erkrankung (CJK) wurde bei der Gruppe der Prionerkrankungen erstmalig beschrieben. Obwohl diese als vergleichsweise selten und exotisch betrachtet werden, hatten sie letztlich einen grosen Stellenwert fur das Verstandnis pathogenetischer Mechanismen bei anderen neurodegenerativen Erkrankungen. more...
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- 2013
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11. Quantifying prion disease penetrance using large population control cohorts
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Sabina Capellari, André G. Uitterlinden, M. Arfan Ikram, Anna Poleggi, Wei Chen, Alison Boyd, Konrad J. Karczewski, Steven A. McCarroll, Sven J. van der Lee, Steven J. Collins, Sabina Eigenbrod, Jamie L. Marshall, Annemieke J. M. Rozemuller, Karen L. Mohlke, Pamela Sklar, Mark J. Daly, Richard Knight, Miguel Calero, Markku Laakso, Robert Kraaij, Sonia M Vallabh, Cornelia M. van Duijn, Tetsuyuki Kitamoto, Jean Philippe Brandel, Daniel G. MacArthur, Stéphane Haïk, Pierluigi Gambetti, Kaitlin E. Samocha, Monkol Lek, Casper Jansen, Kimberly Chambert, Shaun Purcell, Anna K. Kähler, Michael Boehnke, Piero Parchi, Karol Estrada, Claudia Ponto, Linda P.C. Yu, Nobuo Sanjo, Jeroen van Rooij, Anna Ladogana, Hidehiro Mizusawa, Joyce Y. Tung, Yvonne Cohen, Shulin Na Zhang, Janis Blevins, Christina M. Hultman, Masahito Yamada, Elodie Bouaziz-Amar, Anne H. O’Donnell-Luria, Yosikazu Nakamura, Cory Y. McLean, Inga Zerr, Armin Giese, Albert Hofman, Patrick F. Sullivan, Jean-Louis Laplanche, Eric Vallabh Minikel, Jesús de Pedro-Cuesta, Robert G. Will, J. Fah Sathirapongsasuti, Theo F. J. Kraus, Tsuyoshi Hamaguchi, Neurology, Pathology, Amsterdam Neuroscience - Neurodegeneration, Minikel, Eric Vallabh, Vallabh, Sonia M., Lek, Monkol, Estrada, Karol, Samocha, Kaitlin E., Sathirapongsasuti, J. Fah, Mclean, Cory Y., Tung, Joyce Y., Yu, Linda P. C., Gambetti, Pierluigi, Blevins, Jani, Zhang, Shulin, Cohen, Yvonne, Chen, Wei, Yamada, Masahito, Hamaguchi, Tsuyoshi, Sanjo, Nobuo, Mizusawa, Hidehiro, Nakamura, Yosikazu, Kitamoto, Tetsuyuki, Collins, Steven J., Boyd, Alison, Will, Robert G., Knight, Richard, Ponto, Claudia, Zerr, Inga, Kraus, Theo F.J., Eigenbrod, Sabina, Giese, Armin, Calero, Miguel, De Pedro-Cuesta, Jesú, Haïk, Stéphane, Laplanche, Jean-Loui, Bouaziz-Amar, Elodie, Brandel, Jean-Philippe, Capellari, Sabina, Parchi, Piero, Poleggi, Anna, Ladogana, Anna, O'Donnell-Luria, Anne H., Karczewski, Konrad J., Marshall, Jamie L., Boehnke, Michael, Laakso, Markku, Mohlke, Karen L., Kähler, Anna, Chambert, Kimberly, Mccarroll, Steven, Sullivan, Patrick F., Hultman, Christina M., Purcell, Shaun M., Sklar, Pamela, Van Der Lee, Sven J., Rozemuller, Annemieke, Jansen, Casper, Hofman, Albert, Kraaij, Robert, Van Rooij, Jeroen G. J., Ikram, M. Arfan, Uitterlinden, André G., Van Duijn, Cornelia M., Daly, Mark J., Macarthur, Daniel G., Epidemiology, and Internal Medicine more...
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0301 basic medicine ,PROTEIN GENE MUTATION ,CREUTZFELDT-JAKOB-DISEASE ,animal diseases ,Penetrance ,Disease ,Research & Experimental Medicine ,R208H MUTATION ,Prion Diseases ,Cohort Studies ,STRAUSSLER-SCHEINKER-DISEASE ,0302 clinical medicine ,Risk Factors ,Genotype ,Exome sequencing ,Genetics ,education.field_of_study ,FATAL FAMILIAL INSOMNIA ,General Medicine ,11 Medical And Health Sciences ,3. Good health ,Medicine, Research & Experimental ,UNCOMMON POLYMORPHISM RATHER ,Life Sciences & Biomedicine ,Prions ,Population ,Biology ,AMYLOID PRECURSOR GENE ,PRNP GENE ,PRNP ,03 medical and health sciences ,medicine ,Humans ,Genetic Predisposition to Disease ,Allele ,TRANSGENIC MOUSE MODEL ,education ,Fatal familial insomnia ,Science & Technology ,Exome Aggregation Consortium (ExAC) ,Cell Biology ,06 Biological Sciences ,medicine.disease ,POINT MUTATION ,nervous system diseases ,030104 developmental biology ,Case-Control Studies ,Mutation ,030217 neurology & neurosurgery - Abstract
More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance-the probability that a carrier of the purported disease-causing genotype will indeed develop the disease-is generally unknown. We assess the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 population control exomes, and 531,575 individuals genotyped by 23andMe Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the population than expected on the basis of genetic prion disease prevalence. Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from < 0.1 to similar to 100%. We also show that truncating variants in PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, a finding that supports the safety of therapeutic suppression of prion protein expression. more...
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- 2015
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12. A Genome Wide Association Study Links Glutamate Receptor Pathway to Sporadic Creutzfeldt-Jakob Disease Risk
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Jean-Louis Laplanche, Pascual Sánchez-Juan, Olga Calero, Victoria Lewis, Cornelia M. van Duijn, Fernando Rivadeneira, Stéphane Haïk, Onofre Combarros, Anna Poleggi, José Berciano, Jean-Philippe Brandel, Claudia Ponto, André G. Uitterlinden, Robert G. Will, Angel Carracedo, Albert Hofman, Inga Zerr, Thomas Ströbel, Matthew Bishop, Miguel Calero, Steven J. Collins, Herbert Budka, Maurizio Pocchiari, Gabor G. Kovacs, Anna Ladogana, Yurii S. Aulchenko, Alison Boyd, Sven J. van der Lee, Richard Knight, Epidemiology, Internal Medicine, University of Zurich, Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), University of Edinburgh, Medizinische Universität Wien = Medical University of Vienna, Institute of Health 'Carlos III', Erasmus University Medical Center [Rotterdam] (Erasmus MC), Institute of Cytology and Genetics, Russian Academy of Sciences [Moscow] (RAS), Novosibirsk State University (NSU), Instituto Superiore di Sanita Roma, University of Melbourne, DZNE Göttingen, CIBER de Enfermedades Raras (CIBERER), Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de biochimie et biologie moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-IFR139, CIBER de Enfermedades Neurodegenerativas (CIBERNED), Erasmus Medical Center, Erasmus MC - Netherlands, Russian Academy of Sciences [Moscow] ( RAS ), Novosibirsk State University ( NSU ), Center of Excellence in Genomic Medicine Research ( CEGMR ), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP], IFR139-Hôpital Lariboisière-Assistance publique - Hôpitaux de Paris (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), HAL UPMC, Gestionnaire, Scottish Government, Unión Europea. Comisión Europea. 7 Programa Marco, Robert Koch Institute, Federal Ministry for Health (Alemania), Ministero della Salute (Italia), Dutch Research Council (Holanda), National Foundation for the Elderly (Holanda), Erasmus University Rotterdam (Países Bajos), Netherlands Organisation for Health Research and Development, Ministery of Education, Culture and Science (Holanda), Unión Europea. Comisión Europea, Russian Science Foundation, Instituto de salud Carlos III, Australian National Creutzfeldt-Jakob Disease Registry, Commonwealth Fund, and National Health and Medical Research Council (Australia) more...
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PRNP protein, human ,Genome-wide association study ,GRM8 ,methods [Genome-Wide Association Study] ,Receptors, Metabotropic Glutamate ,Creutzfeldt-Jakob Syndrome ,Glutamate ,Receptor ,Creutzfeldt-Jakob Disease ,Germany ,Genotype ,GWAS ,Netherlands ,Genetics ,Multidisciplinary ,metabotropic glutamate receptor 8 ,genetics [Creutzfeldt-Jakob Syndrome] ,3. Good health ,Neurology ,[ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Medicine ,PRNP ,Research Article ,Signal Transduction ,Prions ,Science ,genetics [Receptors, Metabotropic Glutamate] ,10208 Institute of Neuropathology ,Single-nucleotide polymorphism ,610 Medicine & health ,1100 General Agricultural and Biological Sciences ,Biology ,Polymorphism, Single Nucleotide ,Prion Proteins ,Cellular and Molecular Neuroscience ,1300 General Biochemistry, Genetics and Molecular Biology ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Humans ,ddc:610 ,1000 Genomes Project ,Genotyping ,Gene ,1000 Multidisciplinary ,genetics [Prions] ,Glutamate receptor ,United Kingdom ,Metabotropic glutamate receptor ,Case-Control Studies ,Sporadic CJD ,570 Life sciences ,biology ,Genome-Wide Association Study - Abstract
We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62x10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Genomes Project and imputed genotypes from the Rotterdam Study (Total n=12967). The meta-analysis of the results showed that rs6107516 (p-value=3.00x10-8) and rs6951643 (p-value=3.91x10-5) remained as the two most significantly associated SNPs. Rs6951643 is located in an intronic region of GRM8, a gene that was additionally tagged by a cluster of 12 SNPs within our top100 ranked results. GRM8 encodes for mGluR8, a protein which belongs to the metabotropic glutamate receptor family, recently shown to be involved in the transduction of cellular signals triggered by the prion protein. Pathway enrichment analyses performed with both Ingenuity Pathway Analysis and ALIGATOR postulates glutamate receptor signalling as one of the main pathways associated with sCJD. In summary, we have detected GRM8 as a novel, non-PRNP, genome-wide significant marker associated with heightened disease risk, providing additional evidence supporting a role of glutamate receptors in sCJD pathogenesis. This study was supported by: UK: the National CJD Research and Surveillance UK Unit is funded by the Department of Health and the Scottish Government Health Department. The National CJD Research and Surveillance Unit is funded by the Policy Research Programme in the Department of Health. Germany: This work was supported by a grant from the European Commission (Protecting the food chain from prions: shaping European priorities through basic and applied research (PRIORITY, N° 222887) Project number: FP7-KBBE-2007-2A). The study was performed within the recently established Clinical Dementia Center at the University Medical Center Göttingen and was partly supported by grants from the EU Joint Programme – Neurodegenerative Disease Research (JPND - DEMTEST "Biomarker based diagnosis of rapid progressive dementias optimization of diagnostic protocols", 01ED1201A). This study was funded by the Robert Koch Institute through funds from the Federal Ministry of Health (grant no. 1369-341). Italy: The Italian Registry of CJD and related disorders is funded by the Ministry of Health, National Centre for Disease Prevention and Control, Central Actions.This work was partly supported by grant from the EU Joint Programme – Neurodegenerative Disease Research (JPND-DEMTEST “Biomarker based diagnosis of rapid progressive dementias-optimization of diagnostic protocols”, 01ED1201A). The Netherlands: the generation and management of genome-wide association study (GWAS) genotype data for the Rotterdam Study is supported by the Netherlands Organization of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. YSA is supported by Russian Science Foundation (RSCF) grant 14-14-00313. Spain. PSJ was supported by a grant from FIS (PI12/02288) and JPND project DEMTEST (PI11/03028). AC is supported by PI13/01136 Acción Estratégica de Salud del Instituto de Salud Carlos III e INNOPHARMA. Australia: The Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR) is funded by the Commonwealth Department of Health. SJC is supported by a NHMRC Practitioner Fellowship (#APP1005816). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript Sí more...
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- 2015
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13. Cerebrospinal fluid tau levels are a marker for molecular subtype in sporadic Creutzfeldt-Jakob disease
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Saima Zafar, André Karch, Inga Zerr, Annika Müller-Heine, Franc Llorens, Peter Hermann, Amandeep Singh Arora, Matthias Schmitz, Claudia Ponto, and Helmholtz Centre for infection research, Inhoffenstr. 7, D-38124 Braunschweig, Germany. more...
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Male ,Aging ,Pathology ,medicine.medical_specialty ,Genotype ,Prions ,classification [Creutzfeldt-Jakob Syndrome] ,diagnosis [Creutzfeldt-Jakob Syndrome] ,tau Proteins ,Disease ,Biology ,Creutzfeldt-Jakob Syndrome ,Cerebrospinal fluid ,mental disorders ,medicine ,Humans ,In patient ,ddc:610 ,Codon ,Aged ,genetics [Prions] ,General Neuroscience ,Neurodegeneration ,Disease progression ,genetics [Codon] ,classification [Prions] ,Sporadic Creutzfeldt-Jakob disease ,genetics [Creutzfeldt-Jakob Syndrome] ,Middle Aged ,medicine.disease ,Prognosis ,cerebrospinal fluid [Biomarkers] ,cerebrospinal fluid [tau Proteins] ,Disease Progression ,Biomarker (medicine) ,Female ,Neurology (clinical) ,Geriatrics and Gerontology ,Biomarkers ,Developmental Biology - Abstract
The molecular subtype of sporadic Creutzfeldt-Jakob disease (sCJD) is an important prognostic marker for patient survival. However, subtype determination is not possible during lifetime. Because the rate of disease progression is associated with the molecular subtype, this study aimed at investigating if total tau, a marker of neuronal death, allows premortem diagnosis of molecular subtype when codon 129 genotype is known. Two hundred ninety-six sCJD patients were tested for their cerebrospinal fluid total tau level at the time of diagnosis and were investigated for their sCJD subtype postmortem. There was a significant association between tau levels and the prion protein type in patients with codon 129 MM (p < 0.001), MV (p = 0.004), and VV (p = 0.001) genotype. Receiver operating characteristic analyses showed values of area under the curve of 0.76-0.80 for the different genotypes indicating a good diagnostic validity of the test. Total tau can be used as a diagnostic test for the assessment of prion protein type when codon 129 genotype is known. It provides valuable information for physicians and next of kin about the further course of disease. more...
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- 2014
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14. A proposal of new diagnostic pathway for fatal familial insomnia
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Claudia Ponto, Inga Zerr, Daniela Varges, Hans A. Kretzschmar, Walter J. Schulz-Schaeffer, Uta Heinemann, M. Bartl, P. Sanchez Juan, and Anna Krasnianski
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Male ,Pathology ,Pediatrics ,Disease ,Polysomnography ,Creutzfeldt-Jakob Syndrome ,Prion Diseases ,0302 clinical medicine ,Germany ,Family history ,Aged, 80 and over ,0303 health sciences ,medicine.diagnostic_test ,Cognitive Neurology ,DEMENTIA ,CREUTZFELDT-JAKOB DISEASE ,Electroencephalography ,Middle Aged ,Magnetic Resonance Imaging ,3. Good health ,Psychiatry and Mental health ,Predictive value of tests ,Population Surveillance ,Critical Pathways ,Female ,Algorithms ,Adult ,medicine.medical_specialty ,Prions ,Insomnia, Fatal Familial ,Sensitivity and Specificity ,Prion Proteins ,Diagnosis, Differential ,03 medical and health sciences ,Predictive Value of Tests ,mental disorders ,medicine ,Dementia ,Humans ,030304 developmental biology ,Aged ,Fatal familial insomnia ,Tomography, Emission-Computed, Single-Photon ,familial insomnia ,business.industry ,Reproducibility of Results ,medicine.disease ,Positron-Emission Tomography ,Mutation ,Surgery ,Neurology (clinical) ,Differential diagnosis ,business ,030217 neurology & neurosurgery - Abstract
BACKGROUND: In absence of a positive family history, the diagnosis of fatal familial insomnia (FFI) might be difficult because of atypical clinical features and low sensitivity of diagnostic tests. FFI patients usually do not fulfil the established classification criteria for Creutzfeldt-Jakob disease (CJD); therefore, a prion disease is not always suspected. OBJECTIVE: To propose an update of diagnostic pathway for the identification of patients for the analysis of D178-M129 mutation. DESIGN AND METHODS: Data on 41 German FFI patients were analysed. Clinical symptoms and signs, MRI, PET, SPECT, polysomnography, EEG and cerebrospinal fluid biomarkers were studied. RESULTS: An algorithm was developed which correctly identified at least 81% of patients with the FFI diagnosis during early disease stages. It is based on the detection of organic sleep disturbances, either verified clinically or by a polysomnography, and a combination of vegetative and focal neurological signs and symptoms. Specificity of the approach was tested on three cohorts of patients (MM1 sporadic CJD patients, non-selected sporadic CJD and other neurodegenerative diseases). CONCLUSIONS: The proposed scheme may help to improve the clinical diagnosis of FFI. As the sensitivity of all diagnostic tests investigated but polysomnography is low in FFI, detailed clinical investigation is of special importance. peerReviewed more...
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- 2014
15. Report about Four Novel Mutations in the Prion Protein Gene
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Sabina Eigenbrod, Claudia Ponto, Inga Zerr, Eva M. Grasbon-Frodl, Hans A. Kretzschmar, Lena Maria Raddatz, Gabi Schelzke, and Katharina Stoeck
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Male ,medicine.medical_specialty ,Neurology ,Prions ,Cognitive Neuroscience ,animal diseases ,Neurogenetics ,Disease ,medicine.disease_cause ,Creutzfeldt-Jakob Syndrome ,Prion Proteins ,PRNP ,Prion Diseases ,03 medical and health sciences ,0302 clinical medicine ,mental disorders ,medicine ,Humans ,Prion protein ,Gene ,030304 developmental biology ,Aged ,Genetics ,Aged, 80 and over ,0303 health sciences ,Mutation ,business.industry ,Cerebrospinal Fluid Proteins ,Middle Aged ,Phenotype ,3. Good health ,nervous system diseases ,Psychiatry and Mental health ,14-3-3 Proteins ,Prion disease ,Female ,Geriatrics and Gerontology ,business ,030217 neurology & neurosurgery - Abstract
Background/Aims: Since detection of the prion protein gene (PRNP) more than 30 mutations have been discovered. Some have only been found in single case reports without known intrafamilial accumulation or neuropathological proof so that the causal connection between mutation and disease could not be proved. Those patients often present atypical clinical phenotypes, and it is not unusual that they are classified as diseases other than Creutzfeldt-Jakob disease (CJD). Methods: Cases of suspected CJD have been reported to the national reference center for prion diseases. Clinical and diagnostic data were collected, and a classification of definite, possible or probable prion disease was made. Molecular analysis of PRNP was performed by capillary sequencing. Results: We have described 4 cases with atypical clinical and diagnostic findings and unknown mutations in PRNP so far. Conclusion: Three patients fulfilled the criteria of probable CJD, and 1 patient fulfilled the criteria of possible CJD but the clinical picture in none of the patients was typical CJD; hence, it remained questionable whether the mutations were causal of the disease. more...
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- 2012
16. Rare structural genetic variation in human prion diseases
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Simon Mead, John Beck, Holger Hummerich, Ana Lukic, Inga Zerr, Gary Adamson, John Collinge, James Uphill, Mark Poulter, Craig A. Brown, Jerome Whitfield, Claudia Ponto, Sarah E. Lloyd, and Tracy Campbell more...
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Male ,Aging ,animal diseases ,PRNP protein, human ,Loss of Heterozygosity ,parkin protein ,Scrapie ,Genome-wide association study ,Disease ,Creutzfeldt-Jakob Syndrome ,Prion Diseases ,genetics [Kuru] ,Gene duplication ,Copy-number variation ,genetics [Genetic Predisposition to Disease] ,3' Untranslated Regions ,Cells, Cultured ,genetics [Ubiquitin-Protein Ligases] ,Genetics ,education.field_of_study ,Kuru ,General Neuroscience ,genetics [Creutzfeldt-Jakob Syndrome] ,3. Good health ,genetics [3' Untranslated Regions] ,Female ,Risk ,DNA Copy Number Variations ,genetics [DNA Copy Number Variations] ,Prions ,Ubiquitin-Protein Ligases ,Population ,Biology ,Prion Proteins ,PRNP ,genetics [Loss of Heterozygosity] ,genetics [Prion Diseases] ,mental disorders ,medicine ,Humans ,Genetic Predisposition to Disease ,ddc:610 ,education ,Aged ,genetics [Prions] ,medicine.disease ,nervous system diseases ,Neurology (clinical) ,Geriatrics and Gerontology ,Genome-Wide Association Study ,Developmental Biology - Abstract
Prion diseases are a diverse group of neurodegenerative conditions, caused by the templated misfolding of prion protein. Aside from the strong genetic risk conferred by multiple variants of the prion protein gene (PRNP), several other variants have been suggested to confer risk in the most common type, sporadic Creutzfeldt-Jakob disease (sCJD) or in the acquired prion diseases. Large and rare copy number variants (CNVs) are known to confer risk in several related disorders including Alzheimer's disease (at APP), schizophrenia, epilepsy, mental retardation, and autism. Here, we report the first genome-wide analysis for CNV-associated risk using data derived from a recent international collaborative association study in sCJD (n = 1147 after quality control) and publicly available controls (n = 5427). We also investigated UK patients with variant Creutzfeldt-Jakob disease (n = 114) and elderly women from the Eastern Highlands of Papua New Guinea who proved highly resistant to the epidemic prion disease kuru, who were compared with healthy young Fore population controls (n = 395). There were no statistically significant alterations in the burden of CNVs >100, >500, or >1000 kb, duplications, or deletions in any disease group or geographic region. After correction for multiple testing, no statistically significant associations were found. A UK blood service control sample showed a duplication CNV that overlapped PRNP, but these were not found in prion disease. Heterozygous deletions of a 3′ region of the PARK2 gene were found in 3 sCJD patients and no controls (p = 0.001, uncorrected). A cell-based prion infection assay did not provide supportive evidence for a role for PARK2 in prion disease susceptibility. These data are consistent with a modest impact of CNVs on risk of late-onset neurologic conditions and suggest that, unlike APP, PRNP duplication is not a causal high-risk mutation. more...
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- 2015
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17. Replanteando el sentido social de la escuela desde la triada: cuerpo, educación y pandemia
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Claudia Pontón Ramos
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educación ,cuerpo ,escuela y pandemia ,French literature - Italian literature - Spanish literature - Portuguese literature ,PQ1-3999 - Abstract
En este artículo se abordan dos temas centrales, el primero plantea como reto pensar a la escuela y el cuerpo como espacios de aprendizaje; el segundo, refiere a pensar en la alteridad del sujeto y su corporeidad como parte de una construcción discursiva y cultural en permanente cambio. La propuesta reflexiva de estos dos aspectos recupera el vínculo entre el cuerpo, la educación y la pandemia como referentes importantes para identificar elementos significativos orientados a resignificar a la escuela como uno de los contextos principales en los procesos de socialización. Con esto, al dimensionar los efectos y consecuencias de la pandemia nos parece necesario proponer cambios relativos a la configuración escolar y su impacto en la construcción de nuevas subjetividades. Este reto reflexivo exige pensar, tanto a la escuela como al ámbito familiar, como escenarios potenciales para reflexionar sobre la noción de sujeto como proyecto, midiendo las consecuencias de un confinamiento forzado, el cual ha provocado una percepción socio-cultural compleja y desbordante. Atendiendo la línea editorial de este dossier, el artículo intenta articular un análisis teórico y cultural de la escuela en tiempo de pandemia. more...
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- 2022
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18. R47H TREM2 variant increases risk of typical early‐onset Alzheimer's disease but not of prion or frontotemporal dementia
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Sebastian J. Crutch, Jon Beck, Claudia Ponto, Josephine Barnes, Janna Kenny, Colin J. Mahoney, Gary Adamson, Inga Zerr, Kelvin K. Leung, James B. Rowe, Ron Druyeh, Nick C. Fox, Jonathan D. Rohrer, Pierluigi Gambetti, Jennifer M. Nicholas, John Collinge, Martin N. Rossor, Tracy Campbell, Simon Mead, James Uphill, Jonathan M. Schott, Jessica Lowe, Jason D. Warren, Shona Clegg, Hans A. Kretzschmar, Zeinab Abdi, Melanie Blair, Rita Guerreiro, Catherine F. Slattery, and Lorna Harper more...
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Male ,Oncology ,medicine.medical_specialty ,Genotype ,Epidemiology ,Genome-wide association study ,Arginine ,Creutzfeldt-Jakob Syndrome ,Article ,Cohort Studies ,Cellular and Molecular Neuroscience ,Developmental Neuroscience ,Alzheimer Disease ,Risk Factors ,Internal medicine ,medicine ,Humans ,Dementia ,Genetic Predisposition to Disease ,Histidine ,Early-onset Alzheimer's disease ,Receptors, Immunologic ,Psychiatry ,Aged ,Aged, 80 and over ,Membrane Glycoproteins ,business.industry ,TREM2 ,Health Policy ,Brain ,Genetic Variation ,Exons ,Odds ratio ,Middle Aged ,medicine.disease ,3. Good health ,Psychiatry and Mental health ,Phenotype ,Frontotemporal Dementia ,Female ,Neurology (clinical) ,Geriatrics and Gerontology ,Alzheimer's disease ,business ,Genome-Wide Association Study ,Frontotemporal dementia - Abstract
Background Rare TREM2 variants are significant risk factors for Alzheimer's disease (AD). Methods We used next generation sequencing of the whole gene (n = 700), exon 2 Sanger sequencing (n = 2634), p.R47H genotyping (n = 3518), and genome wide association study imputation (n = 13,048) to determine whether TREM2 variants are risk factors or phenotypic modifiers in patients with AD (n = 1002), frontotemporal dementia (n = 358), sporadic (n = 2500), and variant (n = 115) Creutzfeldt-Jakob disease (CJD). Results We confirm only p.R47H as a risk factor for AD (odds ratio or OR = 2.19; 95% confidence interval or CI = 1.04-4.51; P = .03). p.R47H does not significantly alter risk for frontotemporal dementia (OR = 0.81), variant or sporadic CJD (OR = 1.06 95%CI = 0.66-1.69) in our cohorts. Individuals with p.R47H associated AD (n = 12) had significantly earlier symptom onset than individuals with no TREM2 variants (n = 551) (55.2 years vs. 61.7 years, P = .02). We note that heterozygous p.R47H AD is memory led and otherwise indistinguishable from "typical" sporadic AD. Conclusion We find p.R47H is a risk factor for AD, but not frontotemporal dementia or prion disease. more...
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- 2014
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19. Investigating the Association of ApoE Genotypes with Blood-Brain Barrier Dysfunction Measured by Cerebrospinal Fluid-Serum Albumin Ratio in a Cohort of Patients with Different Types of Dementia
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Inga Zerr, Claudia Ponto, Christian Schmidt, Henrike Manthey, Uta Heinemann, André Karch, Peter Hermann, and Klein, Robyn
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Male ,Apolipoprotein E ,Pathology ,Epidemiology ,lcsh:Medicine ,Creutzfeldt-Jakob Syndrome ,0302 clinical medicine ,Cognitive decline ,lcsh:Science ,Aged, 80 and over ,Clinical Chemistry ,0303 health sciences ,Multidisciplinary ,Neurodegenerative Diseases ,Middle Aged ,Dementia ,ApoE Genotypes ,Blood-Brain Barrier Dysfunction ,Cerebrospinal Fluid-Serum Albumin Ratio ,Clinical Laboratory Sciences ,medicine.anatomical_structure ,Neurology ,Blood-Brain Barrier ,Genetic Epidemiology ,Observational Studies ,Medicine ,Female ,Alzheimer's disease ,Research Article ,medicine.medical_specialty ,Genotype ,Clinical Research Design ,Vascular Dementia ,Blood–brain barrier ,03 medical and health sciences ,Apolipoproteins E ,Alzheimer Disease ,Diagnostic Medicine ,Genetic model ,medicine ,Humans ,Risk factor ,Biology ,Aged ,Retrospective Studies ,030304 developmental biology ,Models, Genetic ,Population Biology ,business.industry ,Dementia, Vascular ,lcsh:R ,medicine.disease ,Cross-Sectional Studies ,Immunology ,lcsh:Q ,business ,030217 neurology & neurosurgery - Abstract
Background: Since more than a decade ApoE is known to be a strong risk factor for Alzheimer’s disease (AD); however, molecular pathways mediating this risk are still unclear. In recent years it has been hypothesized that ApoE might play a role in the disintegration of blood-brain barrier (BBB). In the present study we addressed the question if ApoE genotypes might be associated with BBB function measured by albumin ratio (QAlb) in a large cohort of patients with different types of dementia. Methods: Five hundred twenty (520) patients with Creutzfeldt-Jakob disease (CJD, n = 350), Alzheimer’s disease (n = 71) and cerebral small vessel disease (n = 99) were assessed for their ApoE genotype. BBB function was measured in all patients using QAlb and was compared between ApoE genotypes. Dominant and additive genetic models were assumed in order to investigate the potential effect of ApoE on BBB function. Results: We observed no systematic differences in QAlb between ApoE genotypes within the present study. Increased QAlb levels were shown for those without E3 allele in the subgroup of CJD patients when assuming a dominant genetic model (p = 0.035). This could not be confirmed for patients with other forms of dementia (p = 0.234). Discussion: Although there was some evidence for a protective effect of E3 alleles in CJD patients, this study does not support the hypothesis of a systematic role of ApoE genotypes in BBB function in individuals with a diagnosis of dementia. Thus, changes in BBB function do not seem to contribute to the increased risk of cognitive decline associated with certain ApoE genotypes. The interpretation of the results of this study must take into account that BBB function was only assessed by measuring QAlb which has been shown to be a good marker for overall BBB integrity but might not reflect all qualities of the barrier. peerReviewed more...
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- 2013
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20. Ascertainment Bias Causes False Signal of Anticipation in Genetic Prion Disease
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André Karch, Joanna Kenny, Simon Mead, John Collinge, Claudia Ponto, Sven Forner, Leonel T. Takada, Inga Zerr, Steven J. Collins, Jamie Fong, Eric Vallabh Minikel, Alison Boyd, Genevieve M Klug, and Michael D. Geschwind more...
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Male ,PRNP protein, human ,genetics [Anticipation, Genetic] ,Pedigree chart ,Disease ,Medical and Health Sciences ,Creutzfeldt-Jakob Syndrome ,Anticipation ,0302 clinical medicine ,Models ,2.1 Biological and endogenous factors ,Genetics(clinical) ,Aetiology ,Age of Onset ,Child ,Genetics (clinical) ,Genetics & Heredity ,0303 health sciences ,genetics [Creutzfeldt-Jakob Syndrome] ,Statistical ,Biological Sciences ,Middle Aged ,Pedigree ,Infectious Diseases ,Genetic Diseases ,Mutation (genetic algorithm) ,Female ,Adult ,Adolescent ,Prions ,Genetic counseling ,genetics [Mutation] ,Biology ,Article ,Prion Proteins ,PRNP ,03 medical and health sciences ,Young Adult ,Rare Diseases ,Genetic ,Bias ,ddc:570 ,Genetics ,Humans ,Computer Simulation ,030304 developmental biology ,Aged ,Retrospective Studies ,genetics [Genetic Diseases, Inborn] ,Models, Statistical ,Anticipation, Genetic ,genetics [Prions] ,Prevention ,Genetic Diseases, Inborn ,Transmissible Spongiform Encephalopathy (TSE) ,Brain Disorders ,Inborn ,Anticipation (genetics) ,Mutation ,Age of onset ,030217 neurology & neurosurgery ,Demography - Abstract
© 2014 by The American Society of Human Genetics. All rights reserved. Anticipation is the phenomenon whereby age of onset in genetic disease decreases in successive generations. Three independent reports have claimed anticipation in Creutzfeldt-Jakob disease (CJD) caused by the c.598G>A mutation in PRNP encoding a p.Glu200Lys (E200K) substitution in the prion protein. If confirmed, this finding would carry clear implications for genetic counseling. We analyzed pedigrees with this mutation from four prion centers worldwide (n = 217 individuals with the mutation) to analyze age of onset and death in affected and censored individuals. We show through simulation that selective ascertainment of individuals whose onset falls within the historical window since the mutation's 1989 discovery is sufficient to create robust false signals both of anticipation and of heritability of age of onset. In our data set, the number of years of anticipation observed depends upon how strictly the data are limited by the ascertainment window. Among individuals whose disease was directly observed at a study center, a 28-year difference between parent and child age of onset is observed (p = 0.002), but including individuals ascertained retrospectively through family history reduces this figure to 7 years (p = 0.005). Applying survival analysis to the most thoroughly ascertained subset of data eliminates the signal of anticipation. Moreover, even non-CJD deaths exhibit 16 years anticipation (p = 0.002), indicating that ascertainment bias can entirely explain observed anticipation. We suggest that reports of anticipation in genetic prion disease are driven entirely by ascertainment bias. Guidelines for future studies claiming statistical evidence for anticipation are suggested. more...
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