Biochemical features of genetic Creutzfeldt-Jakob disease with valine-to-isoleucine substitution at codon 180 on the prion protein gene.

PubMed

Ito, Yoko; Sanjo, Nobuo; Hizume, Masaki; Kobayashi, Atsushi; Ohgami, Tetsuya; Satoh, Katsuya; Hamaguchi, Tsuyoshi; Yamada, Masahito; Kitamoto, Tetsuyuki; Mizusawa, Hidehiro; Yokota, Takanori

2018-02-19

Valine-to-isoleucine substitution at codon 180 of the prion protein gene is only observed in patients with Creutzfeldt-Jakob disease and accounts for approximately half of all cases of genetic prion disease in Japan. In the present study, we investigated the biochemical characteristics of valine-to-isoleucine substitution at codon 180 in the prion protein gene, using samples obtained from the autopsied brains of seven patients with genetic Creutzfeldt-Jakob disease exhibiting this mutation (diagnoses confirmed via neuropathological examination). Among these patients, we observed an absence of diglycosylated and monoglycosylated forms of PrP res at codon 181. Our findings further indicated that the abnormal prion proteins were composed of at least three components, although smaller carboxyl-terminal fragments were predominant. Western blot analyses revealed large amounts of PrP res in the cerebral neocortices, where neuropathological examination revealed marked spongiosis. Relatively smaller amounts of PrP res were detected in the hippocampus, where milder spongiosis was observed, than in the cerebral neocortex. These findings indicate that abnormal prion proteins in the neocortex are associated with severe toxicity, resulting in severe spongiosis. Our findings further indicate that the valine-to-isoleucine substitution is not a polymorphism, but rather an authentic pathogenic mutation associated with specific biochemical characteristics that differ from those observed in sporadic Creutzfeldt-Jakob disease. Copyright © 2018 Elsevier Inc. All rights reserved.

Clinical Issues-May 2016.

PubMed

Van Wicklin, Sharon A

2016-05-01

Variations in documenting surgical wound classification Key words: surgical wound classification, clean, clean-contaminated, contaminated, dirty. Wearing long-sleeved jackets while preparing and packaging items for sterilization Key words: long-sleeved jackets, organic material, sterile processing. Endoscopic transmission of prions Key words: prions, high-risk tissue, low-risk tissue, Creutzfeldt-Jakob disease (CJD), variant Creutzfeldt-Jakob disease (vCJD). Wearing gloves when handling flexible endoscopes Key words: gloves, low-protein, powder-free, natural rubber latex gloves, latex-free gloves. Copyright © 2016 AORN, Inc. Published by Elsevier Inc. All rights reserved.

Creutzfeldt-Jakob disease with Alzheimer pathology, presenting with status epilepticus following repeated partial seizures: a case report and literature review.

PubMed

Miyake, Keita; Hara, Takashi; Oshima, Etsuko; Kawada, Kiyohiro; Ishizu, Hideki; Yamauchi, Yuko; Satoh, Katsuya; Kitamoto, Tetsuyuki; Takenoshita, Shintaro; Terada, Seishi; Yamada, Norihito

2018-04-25

Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disease. Common first symptoms are dementia, cerebellar ataxia, visual disturbance, and psychiatric symptoms. Seizure as the first symptom of CJD is a very rare finding. We experienced an elderly woman who presented initially with status epilepticus following repeated partial seizures in the course of Alzheimer disease (AD) dementia. Anti-convulsive therapy had no effect. Autopsy revealed definite CJD with AD pathology. This is the first reported CJD case presenting with status epilepticus in the course of AD dementia.

Creutzfeldt-Jakob Disease-Like Periodic Sharp Wave Complexes in Voltage-Gated Potassium Channel-Complex Antibodies Encephalitis: A Case Report.

PubMed

Savard, Martin; Irani, Sarosh R; Guillemette, Annie; Gosselin-Lefebvre, Stéphanie; Geschwind, Michael; Jansen, Gerard H; Gould, Peter V; Laforce, Robert

2016-02-01

Voltage-gated potassium channel-complex antibodies (VGKC-cAbs) encephalitis, a treatable autoantibody encephalopathy, has been previously reported to clinically mimic sporadic Creutzfeldt-Jakob disease. Among available clinical clues to distinguish them, periodic sharp wave complexes, a typical finding in sporadic Creutzfeldt-Jakob disease, have never been reported in association with VGKC-cAbs encephalitis. A 76-year-old man was transferred to a tertiary neurology center with a clinical history of 6-month weight loss, cognitive disturbance, and nonspecific generalized weakness. He had two seizures the month before transfer and then evolved to severe encephalopathy, requiring mechanical ventilation. Periodic sharp wave complexes every 1 to 2 seconds over slowed background were found on EEG, and MRI showed cerebellar and bifrontal cortical T2/FLAIR/DWI hypersignal without restricted diffusion on ADC mapping. Pancorporal positron emission tomography scan was negative. An immunotherapy trial did not improve the patient condition. Therefore, he died after life support withdrawal. Brain autopsy revealed mononuclear neocortex infiltrate without significant spongiosis, and the anti-VGKC test showed a seropositivity of 336 pmol/L (normal, 0-31), 3 month after the patient deceased. This is the first reported case of VGKC-cAbs encephalitis associated with periodic sharp wave complexes on EEG, which further confuse the differential diagnosis with sporadic Creutzfeldt-Jakob disease. However, the cortical DWI hypersignal without restriction seems to remain a way to discriminate these two entities appropriately, when present. These clues are of paramount importance because VGKC-cAbs encephalitis is a treatable disease.

Treating seizures in Creutzfeldt-Jakob disease.

PubMed

Ng, Marcus C; Westover, M Brandon; Cole, Andrew J

2014-01-01

Seizures are known to occur in Creutzfeldt-Jakob disease (CJD). In the setting of a rapidly progressive condition with no effective therapy, determining appropriate treatment for seizures can be difficult if clinical morbidity is not obvious yet the electroencephalogram (EEG) demonstrates a worrisome pattern such as status epilepticus. Herein, we present the case of a 39-year-old man with CJD and electrographic seizures, discuss how this case challenges conventional definitions of seizures, and discuss a rational approach toward treatment. Coincidentally, our case is the first report of CJD in a patient with Stickler syndrome.

[A study of Creutzfeldt-Jakob disease during 1985-96. No indication of cases of the "mad cow disease" in Sweden].

PubMed

Lundberg, P O

1999-02-10

A retrospective study of Creutzfeldt-Jakob disease (CJD) in Sweden during the period 1985-96 yielded an annual incidence of 1.18 per million. Data for incidence, age distribution (at onset and at death), and duration of illness were similar to those of other countries, with the exception of new variant CJD (nvCJD) cases in the UK, and as far as can be judged the symptomatology was also similar. So far, there is no indication of the occurrence of any cases of nvCJD in Sweden.

Thinking the unthinkable: Alzheimer's, Creutzfeldt-Jakob and Mad Cow disease: the age-related reemergence of virulent, foodborne, bovine tuberculosis or losing your mind for the sake of a shake or burger.

PubMed

Broxmeyer, Lawrence

2005-01-01

The possibility of the age-related reemergence of foodborne Mycobacterium bovis (bovine tuberculosis) as a vector for Creutzfeldt-Jakob Disease (CJD or human Mad Cow Disease) and Mad Cow disease itself is real. The CDC reported last May of an outbreak of CJD linked to the consumption of meat contaminated "with the agent causing" bovine spongiform encephalopathy (BSE) in a New Jersey racetrack between the time frame 1995-2004. In the opinion of experts, ample justification exists for considering a similar pathogenesis for Alzheimer's, Creutzfeldt-Jakob and the other spongiform encephalopathies such as Mad Cow disease. In fact, Creutzfeldt-Jakob and Alzheimer's often coexist and at this point are thought to differ merely by time-dependent physical changes. A recent study links up to 13% of all "Alzheimer's" victims as really having Creutzfeldt-Jakob disease. Bovine tuberculosis, which includes Mycobacterium bovis and M. avium-intracellulare or paratuberculosis, is and has always been the most prevalent threat to the cattle industry, and the USDA reports that between 20% and 40% of US dairy herds are infected with paratuberculosis alone. The health risk for milk tainted with M. bovis has been known for decades and there was a time not so long ago when "tuberculin-tested" was printed on every milk container. Schliesser stated that meat from tuberculous animals may also constitute a significant risk of infection. At the turn of the 20th century 25% of the many US deaths from TB in adults were caused by M. bovis. Dairy products aside, when past and present meat consumption are factored in, there is three times the risk of developing Alzheimer's in meat eaters as opposed to vegetarians. The investigation into the causal trail for Creutzfeldt-Jakob, indistinguishable from Alzheimer's except for its shorter, lethal course might have grown cold where it not for Roel's and others who linked mad cow in cattle with M. bovis and related paratuberculosis on clinical, pathologic and epidemiological grounds. The southwest of the UK, the very cradle of British BSE and CJD outbreaks, saw an exponential increase in bovine tuberculosis just prior to it's spongiform outbreaks. All of this brings up the unthinkable: that Alzheimer's, Cruetzfeldt-Jackob, and Mad Cow Disease might just be caused by eating the meat or dairy in consumer products or feed. It is only appropriate therefore to explore the role of bovine TB and the atypical mycobacteria in Alzheimer's, JCD and Mad Cow disease and develop better serological surveillance for these pathogens.

Vision loss due to coincident ocular and central causes in a patient with Heidenhain variant Creutzfeldt-Jakob disease.

PubMed

Foundas, Maria; Donaldson, Mark D; McAllister, Ian L; Bridges, Leslie R

2008-03-01

Creutzfeldt-Jakob disease (CJD) is a degenerative disease of the brain associated with a rapidly progressive spongiform encephalopathy. Visual symptoms and neuro-ophthalmological signs are not infrequent, and presentation to an ophthalmologist may result. A case is reported of an 89-years-old gentleman who presented with a short history of isolated deterioration in vision. He underwent ocular intervention but subsequently developed progressive dementia, asterixis, myoclonus, cerebellar and extrapyramidal signs, and cortical blindness. An electroencephalogram was consistent with CJD. The patient progressively deteriorated and died 9 weeks after symptom onset. Limited post-mortem examination confirmed CJD.

Prolactinoma

MedlinePlus

... Creutzfeldt-Jakob Disease Resource List Health Alert: Adrenal Crisis Causes Death in Some People Who Were Treated ... Health Information Diabetes Digestive Diseases Kidney Disease Weight Management Liver Disease Urologic Diseases Endocrine Diseases Diet & Nutrition ...

Creutzfeldt-Jakob Disease

MedlinePlus

... with infected tissue, usually during a medical procedure Cattle can get a disease related to CJD called bovine spongiform encephalopathy (BSE) or "mad cow disease." There is concern that people can get ...

Creutzfeldt-Jakob disease latest unknown in struggle to restore faith in blood supply.

PubMed Central

Vaughan, P

1996-01-01

There was considerable medical interest in a recent Toronto conference on prion disease--and in Creutzfeldt-Jakob disease (CJD) in particular--because of the recent tainted-beef controversy in Britain. Although there is no proven link between a newly recognized variant form of CJD and "mad cow disease," and no evidence that CJD can be spread through the blood supply, the theoretical risk has scientists scrambling to understand how the disease is spread and policymakers struggling with the thorny issue of whether to notify persons who have received blood or blood products that may place them at risk. Until the mysteries of prion diseases and their transmission are unravelled, Dr. Peter Vaughan reports, physicians and their patients will have to live with uncertainty. Images p566-a PMID:8804263

Normal Pressure Hydrocephalus

MedlinePlus

... NINDS Focus on Disorders Alzheimer's & Related Dementias Epilepsy Parkinson's Disease Spinal Cord Injury Traumatic Brain Injury Focus On ... those of other disorders such as Alzheimer's disease, Parkinson's disease, and Creutzfeldt-Jakob disease, the disorder is often ...

Prion Strain Characterization of a Novel Subtype of Creutzfeldt-Jakob Disease.

PubMed

Galeno, Roberta; Di Bari, Michele Angelo; Nonno, Romolo; Cardone, Franco; Sbriccoli, Marco; Graziano, Silvia; Ingrosso, Loredana; Fiorini, Michele; Valanzano, Angelina; Pasini, Giulia; Poleggi, Anna; Vinci, Ramona; Ladogana, Anna; Puopolo, Maria; Monaco, Salvatore; Agrimi, Umberto; Zanusso, Gianluigi; Pocchiari, Maurizio

2017-06-01

In 2007, we reported a patient with an atypical form of Creutzfeldt-Jakob disease (CJD) heterozygous for methionine-valine (MV) at codon 129 who showed a novel pathological prion protein (PrP TSE ) conformation with an atypical glycoform (AG) profile and intraneuronal PrP deposition. In the present study, we further characterize the conformational properties of this pathological prion protein (PrP TSE MV AG ), showing that PrP TSE MV AG is composed of multiple conformers with biochemical properties distinct from those of PrP TSE type 1 and type 2 of MV sporadic CJD (sCJD). Experimental transmission of CJD-MV AG to bank voles and gene-targeted transgenic mice carrying the human prion protein gene (TgHu mice) showed unique transmission rates, survival times, neuropathological changes, PrP TSE deposition patterns, and PrP TSE glycotypes that are distinct from those of sCJD-MV1 and sCJD-MV2. These biochemical and experimental data suggest the presence of a novel prion strain in CJD-MV AG IMPORTANCE Sporadic Creutzfeldt-Jakob disease is caused by the misfolding of the cellular prion protein, which assumes two different major conformations (type 1 and type 2) and, together with the methionine/valine polymorphic codon 129 of the prion protein gene, contribute to the occurrence of distinct clinical-pathological phenotypes. Inoculation in laboratory rodents of brain tissues from the six possible combinations of pathological prion protein types with codon 129 genotypes results in the identification of 3 or 4 strains of prions. We report on the identification of a novel strain of Creutzfeldt-Jakob disease isolated from a patient who carried an abnormally glycosylated pathological prion protein. This novel strain has unique biochemical characteristics, does not transmit to humanized transgenic mice, and shows exclusive transmission properties in bank voles. The identification of a novel human prion strain improves our understanding of the pathogenesis of the disease and of possible mechanisms of prion transmission. Copyright © 2017 American Society for Microbiology.

Creutzfeldt-Jakob disease

MedlinePlus

... be the same one that causes vCJD in humans. Variant CJD causes less than 1% of all ... Scrapie (found in sheep) Other very rare inherited human diseases, such as Gerstmann-Straussler-Scheinker disease and ...

Creutzfeldt-Jakob Disease

MedlinePlus

... vCJD) can be acquired by eating meat from cattle affected by a disease similar to CJD called bovine spongiform encephalopathy (BSE) or, commonly, “mad cow” disease. CJD belongs to a family of human ...

Recent US Case of Variant Creutzfeldt-Jakob Disease-Global Implications.

PubMed

Maheshwari, Atul; Fischer, Michael; Gambetti, Pierluigi; Parker, Alicia; Ram, Aarthi; Soto, Claudio; Concha-Marambio, Luis; Cohen, Yvonne; Belay, Ermias D; Maddox, Ryan A; Mead, Simon; Goodman, Clay; Kass, Joseph S; Schonberger, Lawrence B; Hussein, Haitham M

2015-05-01

Variant Creutzfeldt-Jakob disease (vCJD) is a rare, fatal prion disease resulting from transmission to humans of the infectious agent of bovine spongiform encephalopathy. We describe the clinical presentation of a recent case of vCJD in the United States and provide an update on diagnostic testing. The location of this patient's exposure is less clear than those in the 3 previously reported US cases, but strong evidence indicates that exposure to contaminated beef occurred outside the United States more than a decade before illness onset. This case exemplifies the persistent risk for vCJD acquired in unsuspected geographic locations and highlights the need for continued global surveillance and awareness to prevent further dissemination of vCJD.

Creutzfeldt-Jakob disease with mixed transcortical aphasia: insights into echolalia.

PubMed

McPherson, S E; Kuratani, J D; Cummings, J L; Shih, J; Mischel, P S; Vinters, H V

1994-01-01

Aphasia is a common manifestation of Creutzfeldt-Jakob disease (CJD), and investigation of the linguistic disorders of CJD patients may provide insights into the neurobiological mechanisms of language and aphasia. We report an autopsy-confirmed case of CJD in which the presenting symptom was change in language abilities. The patient ultimately evidenced mixed transcortical aphasia (MTA) with echolalia. Disruption of frontal-subcortical circuits with environmental dependency accounts for the symptoms in MTA, including intact repetition and echolalia. Observation in this patient and a review of the literature suggest that frontal-subcortical circuit dysfunction may contribute to the syndrome of echolalia. This hypothesis offers an alternative explanation to "isolation" of the speech area as the cause of MTA.

Sleep-wake disturbances in sporadic Creutzfeldt-Jakob disease.

PubMed

Landolt, H-P; Glatzel, M; Blättler, T; Achermann, P; Roth, C; Mathis, J; Weis, J; Tobler, I; Aguzzi, A; Bassetti, C L

2006-05-09

The prevalence and characteristics of sleep-wake disturbances in sporadic Creutzfeldt-Jakob disease (sCJD) are poorly understood. Seven consecutive patients with definite sCJD underwent a systematic assessment of sleep-wake disturbances, including clinical history, video-polysomnography, and actigraphy. Extent and distribution of neurodegeneration was estimated by brain autopsy in six patients. Western blot analyses enabling classification and quantification of the protease-resistant isoform of the prion protein, PrPSc, in thalamus and occipital cortex was available in four patients. Sleep-wake symptoms were observed in all patients, and were prominent in four of them. All patients had severe sleep EEG abnormalities with loss of sleep spindles, very low sleep efficiency, and virtual absence of REM sleep. The correlation between different methods to assess sleep-wake functions (history, polysomnography, actigraphy, videography) was generally poor. Brain autopsy revealed prominent changes in cortical areas, but only mild changes in the thalamus. No mutation of the PRNP gene was found. This study demonstrates in sporadic Creutzfeldt-Jakob disease, first, the existence of sleep-wake disturbances similar to those reported in fatal familial insomnia in the absence of prominent and isolated thalamic neuronal loss, and second, the need of a multimodal approach for the unambiguous assessment of sleep-wake functions in these patients.

[From the Scrapie syndrome of sheep and goat to the mad cow disease - the history of the discovery of prion].

PubMed

Liu, Rui; Weng, Yi

2009-05-01

Since the discovery of Scrapie Syndrome in sheep and goats in 1730, there emerged a series of diseases such as Creutzfeldt-Jakob disease, kuru disease and mad cow disease etc. In the research of kuru disease, the American scientist D. Carlteton Gajdusek found a new virus without the characteristic of DNA and RNA, which was awarded the Nobel Prize in physiology in 1976. Since then another American scientist, Stanley B. Prusiner, found a new virus-prion, taking protein as the genetic medium, which was awarded the Nobel prize in physiology and medicine in 1997. The discovery of prion is a great landmark in the research of life science, which laid a theoretical foundation for people to conquer a series of diseases such as Scrapie syndrome in sheep and goats, Creutzfeldt-Jakob disease, kuru disease and mad cow disease etc.

Creutzfeldt-Jakob Disease

MedlinePlus

... CJD: Electroencephalogram (EEG) measures the brain's patterns of electrical activity similar to the way an electrocardiogram (ECG) measures the heart's electrical activity. Brain magnetic resonance imaging (MRI) can detect ...

Recent US Case of Variant Creutzfeldt-Jakob Disease—Global Implications

PubMed Central

Fischer, Michael; Gambetti, Pierluigi; Parker, Alicia; Ram, Aarthi; Soto, Claudio; Concha-Marambio, Luis; Cohen, Yvonne; Belay, Ermias D.; Maddox, Ryan A.; Mead, Simon; Goodman, Clay; Kass, Joseph S.; Schonberger, Lawrence B.; Hussein, Haitham M.

2015-01-01

Variant Creutzfeldt-Jakob disease (vCJD) is a rare, fatal prion disease resulting from transmission to humans of the infectious agent of bovine spongiform encephalopathy. We describe the clinical presentation of a recent case of vCJD in the United States and provide an update on diagnostic testing. The location of this patient’s exposure is less clear than those in the 3 previously reported US cases, but strong evidence indicates that exposure to contaminated beef occurred outside the United States more than a decade before illness onset. This case exemplifies the persistent risk for vCJD acquired in unsuspected geographic locations and highlights the need for continued global surveillance and awareness to prevent further dissemination of vCJD. PMID:25897712

Creutzfeldt-Jakob Disease Fact Sheet for Healthcare Workers and Morticians

MedlinePlus

... of CJD (vCJD), largely in Britain, to mad cow disease (bovine spongiform encephalopathy or BSE), a deadly brain disease- similar to CJD-that affects cattle. While there is still no definitive evidence for ...

Results of quinacrine administration to patients with Creutzfeldt-Jakob disease.

PubMed

Nakajima, Masashi; Yamada, Tatsuo; Kusuhara, Tomohiko; Furukawa, Hisako; Takahashi, Mitsuo; Yamauchi, Atsushi; Kataoka, Yasufumi

2004-01-01

Several chemicals inhibit the accumulation of abnormal prion proteins in vitro. We administered one, the antimalarial agent quinacrine, to three patients with sporadic Creutzfeldt-Jakob disease (CJD) and to one with iatrogenic CJD. Quinacrine at 300 mg/day was given enterally for 3 months. Within 2 weeks of administration, the arousal level of the patient with akinetic mutism improved. The other 3 patients, insensible before treatment, had integrative responses such as eye contact or voluntary movement in response to verbal and/or visual stimuli restored. Clinical improvement was transient, lasting 1-2 months during treatment. Quinacrine was well tolerated, except for liver dysfunction and yellowish pigmentation. Although its antiprion activity in the human brain has yet to be proved, these modest effects of quinacrine suggest the possibility of using chemical intervention against prion diseases. Copyright 2004 S. Karger AG, Basel

Proteomics analyses for the global proteins in the brain tissues of different human prion diseases.

PubMed

Shi, Qi; Chen, Li-Na; Zhang, Bao-Yun; Xiao, Kang; Zhou, Wei; Chen, Cao; Zhang, Xiao-Mei; Tian, Chan; Gao, Chen; Wang, Jing; Han, Jun; Dong, Xiao-Ping

2015-04-01

Proteomics changes of brain tissues have been described in different neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. However, the brain proteomics of human prion disease remains less understood. In the study, the proteomics patterns of cortex and cerebellum of brain tissues of sporadic Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD were analyzed with isobaric tags for relative and absolute quantitation combined with multidimensional liquid chromatography and MS analysis, with the brains from three normal individuals as controls. Global protein profiling, significant pathway, and functional categories were analyzed. In total, 2287 proteins were identified with quantitative information both in cortex and cerebellum regions. Cerebellum tissues appeared to contain more up- and down-regulated proteins (727 proteins) than cortex regions (312 proteins) of Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD. Viral myocarditis, Parkinson's disease, Alzheimer's disease, lysosome, oxidative phosphorylation, protein export, and drug metabolism-cytochrome P450 were the most commonly affected pathways of the three kinds of diseases. Almost coincident biological functions were identified in the brain tissues of the three diseases. In all, data here demonstrate that the brain tissues of Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD have obvious proteomics changes at their terminal stages, which show the similarities not only among human prion diseases but also with other neurodegeneration diseases. This is the first study to provide a reference proteome map for human prion diseases and will be helpful for future studies focused on potential biomarkers for the diagnosis and therapy of human prion diseases. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Genetic Characterization of Movement Disorders and Dementias

ClinicalTrials.gov

2018-05-10

Ataxia; Dystonia; Parkinson's Disease; Amyotrophic Lateral Sclerosis; Corticobasal Degeneration; Multiple System Atrophy; Alzheimer's Disease; Lewy Body Dementia; Parkinson Disease-Dementia; Dentatorubral-pallidoluysian Atrophy; Creutzfeldt-Jakob Disease and Fatal Familial Insomnia; Fragile X-associated Tremor/Ataxia Syndrome; Krabbe's Disease; Niemann-Pick Disease, Type C; Neuronal Ceroid Lipofuscinosis

New variant of Creutzfeldt-Jakob (vCJD) disease and other human prion diseases under epidemiological surveillance in Brazil.

PubMed

Gattás, Vera Lúcia; Lima Neto, Antonio Silva; Dimech, George Santiago; Mancini, Denise; Cantarino, Ligia Maria; Marins, José Ricardo Pio; Luna, Expedito José Albuquerque

2007-01-01

To increase the timeliness of detection of human cases of the new variant of Creutzfeldt-Jakob disease (vCJD) and to reduce the risk of transmission, the Brazilian Ministry of Health has established and standardized rules and control measures. These include the definition of criteria for suspect cases, reporting, monitoring, and control measures for illness prevention and transmission. Guidelines to be used by the team of health care staff were published and distributed to health workers. A detailed proposal for a simplified system of surveillance for prion diseases was developed and mandatory reporting introduced. Additional effort is necessary to increase vCJD case detection, thus making it necessary to establish a partnership with health care services for best identification of suspected cases and dissemination of information to all involved in the service dealing with vCJD investigation.

New variant of Creutzfeldt-Jakob (vCJD) disease and other human prion diseases under epidemiological surveillance in Brazil

PubMed Central

Gattás, Vera Lúcia; Lima Neto, Antonio Silva; Dimech, George Santiago; Mancini, Denise; Cantarino, Ligia Maria; Marins, José Ricardo Pio; Luna, Expedito José Albuquerque

2007-01-01

To increase the timeliness of detection of human cases of the new variant of Creutzfeldt-Jakob disease (vCJD) and to reduce the risk of transmission, the Brazilian Ministry of Health has established and standardized rules and control measures. These include the definition of criteria for suspect cases, reporting, monitoring, and control measures for illness prevention and transmission. Guidelines to be used by the team of health care staff were published and distributed to health workers. A detailed proposal for a simplified system of surveillance for prion diseases was developed and mandatory reporting introduced. Additional effort is necessary to increase vCJD case detection, thus making it necessary to establish a partnership with health care services for best identification of suspected cases and dissemination of information to all involved in the service dealing with vCJD investigation. PMID:29213409

Detecting and quantifying prions: Mass spectrometry-based approaches

USDA-ARS?s Scientific Manuscript database

Prions are novel pathogens that cause a set of rare fatal neurological diseases know as transmissible spongiform encephalopathies. Examples of these diseases include Creutzfeldt-Jakob disease, scrapie and chronic wasting disease. Prions are able to recruit a normal cellular prion protein and convert...

Creutzfeldt-Jakob Disease

MedlinePlus

... damage leads to rapid decline in thinking and reasoning as well as involuntary muscle movements, confusion, difficulty ... been tested but have not shown any benefit. Clinical studies of potential CJD treatments are complicated by ...

Unique inflammatory RNA profiles of microglia in Creutzfeldt-Jakob disease

NASA Astrophysics Data System (ADS)

Baker, Christopher A.; Manuelidis, Laura

2003-01-01

Previous studies in Creutzfeldt-Jakob disease (CJD) have shown that myeloid cells in the periphery as well as derivative microglial cells in the brain are infectious. Microglia can show an activated phenotype before prion protein (PrP) pathology is detectable in brain, and isolated infectious microglia contain very little PrP. To find whether a set of inflammatory genes are significantly induced or suppressed with infection, we analyzed RNA from isolated microglia with relevant cDNA arrays, and identified 30 transcripts not previously examined in any transmissible spongiform encephalopathy. This CJD expression profile contrasted with that of uninfected microglia exposed to prototypic inflammatory stimuli such as lipopolysaccharide and IFN-, as well as PrP amyloid. These findings underscore inflammatory pathways evoked by the infectious agent in brain. Transcript profiles unique for CJD microglia and other myeloid cells provide opportunities for more sensitive preclinical diagnoses of infectious and noninfectious neurodegenerative diseases.

[Based on the incidence of Creutzfeldt-Jakob disease in the Lanzarote healthcare area. Description of two definitive cases].

PubMed

Hernández-Ramos, F J; Martínez Martín, M; Esteban Robayna, M; Jensen Toll, F; Palacios Llopis, S

2005-01-01

We present two cases who have been diagnosed of definitive Creutzfeldt-Jakob disease in the health area of Lanzarote in the period January 2002 to January 2004. The two cases are presented with clinical description, complementary tests -- including electroencephalogram, 14-3-3 protein determination -- study of the prionic protein gene, and histopathologic findings. In this article, we try to show the importance of trying to reach a definitive diagnosis with the histopathologic study once there is clinical suspicion (a diagnosis that is probable or possible). In addition our cases show that communication between the clinical and the epidemiological coordinator of the regional community and the National Center of Epidemiology is very important. We refer to the clear growth in the incidence of the disease in the population of Lanzarote in the period above mentioned. Finally, we discuss whether this growth is or is not an isolated event.

Prion diseases in humans: an update.

PubMed

Butler, Rob

2006-10-01

The year 2006 marks 20 years from the first identified bovine spongiform encephalitis in cows and 10 years from the first description of variant Creutzfeldt-Jakob disease in humans. The threatened epidemic in humans now appears unlikely, but psychiatrists need to be aware of recent developments in prion diseases.

76 FR 38667 - Transmissible Spongiform Encephalopathies Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-01

...: The committee will discuss donor deferral for time spent in Saudi Arabia to reduce the risk of variant Creutzfeldt-Jakob disease (vCJD) by blood and blood products and human cells, tissues and cellular and tissue...

Can Creutzfeldt-Jakob disease unravel the mysteries of Alzheimer?

PubMed

Kovacs, Gabor G

2016-09-02

Recent studies on iatrogenic Creutzfeldt-Jakob disease (CJD) raised concerns that one of the hallmark lesions of Alzheimer disease (AD), amyloid-β (Aβ), may be transmitted from human-to-human. The neuropathology of AD-related lesions is complex. Therefore, many aspects need to be considered in deciding on this issue. Observations of recent studies can be summarized as follows: 1) The frequency of iatrogenic CJD cases with parencyhmal and vascular Aβ deposits is statistically higher than expected; 2) The morphology and distribution of Aβ deposition may show distinct features; 3) The pituitary and the dura mater themselves may serve as potential sources of Aβ seeds; 4) Cadaveric dura mater from 2 examined cases shows Aβ deposition; and 5) There is a lack of evidence that the clinical phenotype of AD appears following the application of cadaveric pituitary hormone or dura mater transplantation. These studies support the notion that neurodegenerative diseases have common features regarding propagation of disease-associated proteins as seeds. However, until further evidence emerges, prions of transmissible spongiform encephalopathies are the only neurodegenerative disease-related proteins proven to propagate clinicopathological phenotypes.

Transmission of scrapie prions to primate after an extended silent incubation period

USDA-ARS?s Scientific Manuscript database

Classical bovine spongiform encephalopathy (c-BSE) is an animal prion disease that also causes variant Creutzfeldt-Jakob disease in humans. Over the past decades, c-BSE's zoonotic potential has been the driving force in establishing extensive protective measures for animal and human health. In compl...

A low molecular-weight ferroxidase is increased in the CSF of sCJD cases: CSF ferroxidase and transferrin as diagnostic biomarkers for sCJD

USDA-ARS?s Scientific Manuscript database

Imbalance of brain iron homeostasis is a common feature of neurodegenerative conditions that include sporadic Creutzfeldt-Jakob disease (sCJD), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease, among others. However, the mechanisms underlying this change are unclear. In s...

Food Safety: Bovine Spongiform Encephalopathy (Mad Cow Disease).

PubMed

Acheson, David W. K.

2002-01-01

Bovine spongiform encephalopathy is just one of a group of diseases known as transmissible spongiform encephalopathies. Only recently has it become recognized that transmissible spongiform encephalopathies are likely due to proteins known as prions. Although it has been recognized that transmissible spongiform encephalopathies may readily spread within species, the recent observations that bovine spongiform encephalopathy in cattle may have originated from another transmissible spongiform encephalopathy in sheep, known as scrapie, is cause for concern. Further, bovine spongiform encephalopathy has now been strongly linked with a universally fatal human neurologic disease known as new variant Creutzfeldt-Jakob disease. Currently the only approach to preventing bovine spongiform encephalopathy, and subsequent new variant Creutzfeldt-Jakob disease in humans, from ingestion of bovine spongiform encephalopathy-infected material is to avoid consumption of contaminated food. Little can be done to treat food that will destroy prions and leave a palatable product. At this stage we are continuing to learn about transmissible spongiform encephalopathies and their implications on human health. This is an ever-changing situation and has an unpredictable element in terms of the extent of the current outbreaks in England and other parts of Europe.

Codon 219 polymorphism of PRNP in healthy caucasians and Creutzfeldt-Jakob disease patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Petraroli, R.; Pocchiari, M.

1996-04-01

A number of point and insert mutations of the PrP gene (PRNP) have been linked to familial Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Scheinker disease (GSS). Moreover, the methionine/valine homozygosity at the polymorphic codon 129 of PRNP may cause a predisposition to sporadic and iatrogenic CJD or may control the age at onset of familial cases carrying either the 144-bp insertion or codon 178, codon 198, and codon 210 pathogenic mutations in PRNP. In addition, the association of methionine or valine at codon 129 and the point mutation at codon 178 on the same allele seem to play an important role inmore » determining either fatal familial insomnia or CJD. However, it is noteworthy that a relationship between codon 129 polymorphism and accelerated pathogenesis (early age at onset or shorter duration of the disease) has not been seen in familial CJD patients with codon 200 mutation or in GSS patients with codon 102 mutation, arguing that other, as yet unidentified, gene products or environmental factors, or both, may influence the clinical expression of these diseases. 17 refs.« less

Detection of PrP(Sc) in peripheral tissues of clinically affected cattle after oral challenge with bovine spongiform encephalopathy

USDA-ARS?s Scientific Manuscript database

Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative prion disease that affects cattle and can be transmitted to human beings as new variant Creutzfeldt-Jakob disease (vCJD). A protease-resistant, disease-associated isoform of the prion protein (PrP**Sc) accumulates in the central ner...

New variant CJD-BSE (mad cow disease). The need for disposable ENT instruments.

PubMed

Bingham, Brian

2002-02-25

This paper outlines the development of Bovine Spongiform Encephalopathy (BSE) in the United Kingdom. The relationship between BSE and new variant Creutzfeldt-Jakob disease (vCJD) is considered and the risks of iatrogenic spread reviewed. The rationale for disposable surgical instruments in adenotonsillectomy to prevent iatrogenic spread is discussed.

Creutzfeldt-Jakob disease with severe involvement of cerebral white matter and cerebellum.

PubMed

Berciano, J; Berciano, M T; Polo, J M; Figols, J; Ciudad, J; Lafarga, M

1990-01-01

We describe a patient with Creutzfeldt-Jakob disease (CJD) of the ataxic and panencephalopathic type. Postmortem examination revealed the characteristic lesions of CJD in the grey matter and profound white matter involvement was seen with immunocytochemical techniques. Ultrastructural white matter lesions were identical to those described in experimentally transmitted CJD. There was marked loss of cerebellar granule cells with virtual disappearance of parallel fibres, but Purkinje cells were only slightly reduced. Electron microscopic studies revealed extensive degenerative changes including cytoplasmic vacuoles in both cell types. Silver methods disclosed massive impregnation of white matter and striking abnormalities of Purkinje cells consisting of hypertrophy and flattening of thick dendritic branches, reduction in the number of terminal branchlets, segmentary loss of spines and polymorphic spines. These findings show the extensive involvement of all three cerebellar cortical layers and the reactive plasticity of Purkinje cells to deafferentiation. They favour the hypothesis that demyelination represents a primary lesion of the white matter.

Creutzfeldt-Jakob disease in United Kingdom patients treated with human pituitary growth hormone.

PubMed

Swerdlow, A J; Higgins, C D; Adlard, P; Jones, M E; Preece, M A

2003-09-23

To investigate risk factors for Creutzfeldt-Jakob disease (CJD) in patients in the United Kingdom treated with human pituitary growth hormone (hGH). Incidence rates of CJD, based on person-year denominators, were assessed in a cohort of 1,848 patients treated with hGH in the United Kingdom from 1959 through 1985 and followed to the end of 2000. CJD developed in 38 patients. Risk of CJD was significantly increased by treatment with hGH prepared by the Wilhelmi method of extraction from human pituitaries. Risk was further raised if this treatment was administered at ages 8 to 10 years. The peak risk of CJD was estimated to occur 20 years after first exposure, and the estimated lifetime cumulative risk of CJD in Wilhelmi-treated patients was 4.5%. Size-exclusion chromatography, used in non-Wilhelmi preparation methods, may prevent CJD infection. Susceptibility to CJD may vary with age, and susceptibility may be present in only a few percent of the population.

Protective Effect of Val129-PrP against Bovine Spongiform Encephalopathy but not Variant Creutzfeldt-Jakob Disease

PubMed Central

Fernández-Borges, Natalia; Espinosa, Juan Carlos; Marín-Moreno, Alba; Aguilar-Calvo, Patricia; Asante, Emmanuel A.; Kitamoto, Tetsuyuki; Mohri, Shirou; Andréoletti, Olivier

2017-01-01

Bovine spongiform encephalopathy (BSE) is the only known zoonotic prion that causes variant Creutzfeldt-Jakob disease (vCJD) in humans. The major risk determinant for this disease is the polymorphic codon 129 of the human prion protein (Hu-PrP), where either methionine (Met129) or valine (Val129) can be encoded. To date, all clinical and neuropathologically confirmed vCJD cases have been Met129 homozygous, with the exception of 1 recently reported Met/Val heterozygous case. Here, we found that transgenic mice homozygous for Val129 Hu-PrP show severely restricted propagation of the BSE prion strain, but this constraint can be partially overcome by adaptation of the BSE agent to the Met129 Hu-PrP. In addition, the transmission of vCJD to transgenic mice homozygous for Val129 Hu-PrP resulted in a prion with distinct strain features. These observations may indicate increased risk for vCJD secondary transmission in Val129 Hu-PrP–positive humans with the emergence of new strain features. PMID:28820136

The Canadian Management of Bovine Spongiform Encephalopathy in Historical and Scientific Perspective, 1990-2014.

PubMed

Quimby, Alexandra E; Shamy, Michel C F

2015-11-01

On February 11, 2015, the Canadian Food Inspection Agency announced that a cow born and raised in Alberta had tested positive for bovine spongiform encephalopathy (BSE), commonly known as mad cow disease. BSE is a prion disease of cattle that, when transmitted to humans, produces a fatal neurodegenerative disease known as variant Creutzfeldt-Jakob disease. We believe that this latest case of BSE in Canadian cattle suggests the timeliness of a review of the management of BSE in Canada from a historically and scientifically informed perspective. In this article, we ask: how did the Canadian management of BSE between 1990 and 2014 engage with the contemporary understanding of BSE's human health implications? We propose that Canadian policies largely ignored the implicit medical nature of BSE, treating it as a purely agricultural and veterinary issue. In this way, policies to protect Canadians were often delayed and incomplete, in a manner disturbingly reminiscent of Britain's failed management of BSE. Despite assurances to the contrary, it is premature to conclude that BSE (and with it the risk of variant Creutzfeldt-Jakob disease) is a thing of Canada's past: BSE remains very much an issue in Canada's present.

75 FR 55803 - Transmissible Spongiform Encephalopathies Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-14

... Creutzfeldt-Jakob disease (vCJD) agent in U.S.-licensed plasma-derived Factor VIII and (2) labeling of blood and blood components and plasma-derived products, including plasma-derived albumin and products..., the Committee will hear informational presentations related to FDA's geographic donor deferral policy...

Chronic wasting disease and atypical forms of BSE and scrapie are not transmissible to mice expressing wild-type levels of human PrP

USDA-ARS?s Scientific Manuscript database

The association between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) has demonstrated that cattle TSEs can pose a risk to human health and raises the possibility that other ruminant TSEs may be transmissible to humans. In recent years, several new TSEs in shee...

A case cluster of variant Creutzfeldt-Jakob disease linked to the Kingdom of Saudi Arabia.

PubMed

Coulthart, Michael B; Geschwind, Michael D; Qureshi, Shireen; Phielipp, Nicolas; Demarsh, Alex; Abrams, Joseph Y; Belay, Ermias; Gambetti, Pierluigi; Jansen, Gerard H; Lang, Anthony E; Schonberger, Lawrence B

2016-10-01

As of mid-2016, 231 cases of variant Creutzfeldt-Jakob disease-the human form of a prion disease of cattle, bovine spongiform encephalopathy-have been reported from 12 countries. With few exceptions, the affected individuals had histories of extended residence in the UK or other Western European countries during the period (1980-96) of maximum global risk for human exposure to bovine spongiform encephalopathy. However, the possibility remains that other geographic foci of human infection exist, identification of which may help to foreshadow the future of the epidemic. We report results of a quantitative analysis of country-specific relative risks of infection for three individuals diagnosed with variant Creutzfeldt-Jakob disease in the USA and Canada. All were born and raised in Saudi Arabia, but had histories of residence and travel in other countries. To calculate country-specific relative probabilities of infection, we aligned each patient's life history with published estimates of probability distributions of incubation period and age at infection parameters from a UK cohort of 171 variant Creutzfeldt-Jakob disease cases. The distributions were then partitioned into probability density fractions according to time intervals of the patient's residence and travel history, and the density fractions were combined by country. This calculation was performed for incubation period alone, age at infection alone, and jointly for incubation and age at infection. Country-specific fractions were normalized either to the total density between the individual's dates of birth and symptom onset ('lifetime'), or to that between 1980 and 1996, for a total of six combinations of parameter and interval. The country-specific relative probability of infection for Saudi Arabia clearly ranked highest under each of the six combinations of parameter × interval for Patients 1 and 2, with values ranging from 0.572 to 0.998, respectively, for Patient 2 (age at infection × lifetime) and Patient 1 (joint incubation and age at infection × 1980-96). For Patient 3, relative probabilities for Saudi Arabia were not as distinct from those for other countries using the lifetime interval: 0.394, 0.360 and 0.378, respectively, for incubation period, age at infection and jointly for incubation and age at infection. However, for this patient Saudi Arabia clearly ranked highest within the 1980-96 period: 0.859, 0.871 and 0.865, respectively, for incubation period, age at infection and jointly for incubation and age at infection. These findings support the hypothesis that human infection with bovine spongiform encephalopathy occurred in Saudi Arabia. © Her Majesty the Queen in Right of Canada 2016. Reproduced with the permission of the Minister of Public Health.

Notifying patients exposed to blood products associated with Creutzfeldt-Jakob disease: integrating science, legal duties and ethical mandates

PubMed Central

Caulfield, T; Dossetor, J; Boshkov, L; Hannon, J; Sawyer, D; Robertson, G

1997-01-01

The issue of notifying people who have been exposed to blood products that have been associated with Creutzfeldt-Jakob disease (CJD) has arisen at a time when the Canadian blood system is under intense scrutiny. As a result, the Canadian Red Cross Society issued a recommendation to health care institutions that recipients of CJD-associated blood products be identified, notified and counselled. Although Canadian jurisprudence in the realm of informed consent may support a policy of individual notification, a review of the scientific evidence and the applicable ethical principles arguably favours a policy of a more general public notification. Indeed, situations such as this require a unique approach to the formation of legal and ethical duties, one that effectively integrates all relevant factors. As such, the authors argue that individual notification is currently not justified. Nevertheless, if a system of general notification is implemented (e.g., through a series of public health announcements), it should provide, for people who wish to know, the opportunity to find out whether they were given CJD-associated products. PMID:9371070

Management of neurosurgical instruments and patients exposed to Creutzfeldt-Jakob disease.

PubMed

Belay, Ermias D; Blase, Jennifer; Sehulster, Lynne M; Maddox, Ryan A; Schonberger, Lawrence B

2013-12-01

To summarize the approaches used to manage exposure of patients to inadequately sterilized neurosurgical instruments contaminated as a result of Creutzfeldt-Jakob disease (CJD). Information on past CJD exposure incidents reported to the Centers for Disease Control and Prevention (CDC) was aggregated and summarized. In addition, inactivation studies were reviewed, and data from selected publications were provided for reference. Nineteen incidents of patient exposure to potentially CJD-contaminated instruments were reported to the CDC, including 17 that involved intracranial procedures and 2 that involved ophthalmologic procedures. In more than 50% of incidents, the neurosurgical procedures were performed for diagnostic work up of the index patients. At least 12 of the hospitals had multiple neurosurgical sets, and the CJD-contaminated instruments could not be identified in 11 of 19 hospitals. In 12 of 15 hospitals with neurosurgical incidents, a decision was made to notify patients of their potential exposure. Neurosurgical instruments used for treatment of patients with suspected or diagnosed CJD or patients whose diagnosis is unclear should be promptly identified and sterilized using recommended CJD decontamination protocols. Inability to trace instruments complicates appropriate management of exposure incidents. The feasibility of instituting instrument tracking procedures should be considered.

Management of Neurosurgical Instruments and Patients Exposed to Creutzfeldt-Jakob Disease

PubMed Central

Belay, Ermias D.; Blase, Jennifer; Sehulster, Lynne M.; Maddox, Ryan A.; Schonberger, Lawrence B.

2015-01-01

OBJECTIVE To summarize the approaches used to manage exposure of patients to inadequately sterilized neurosurgical instruments contaminated as a result of Creutzfeldt-Jakob disease (CJD). METHODS Information on past CJD exposure incidents reported to the Centers for Disease Control and Prevention (CDC) was aggregated and summarized. In addition, inactivation studies were reviewed, and data from selected publications were provided for reference. RESULTS Nineteen incidents of patient exposure to potentially CJD-contaminated instruments were reported to the CDC, including 17 that involved intracranial procedures and 2 that involved ophthalmologic procedures. In more than 50% of incidents, the neurosurgical procedures were performed for diagnostic work up of the index patients. At least 12 of the hospitals had multiple neurosurgical sets, and the CJD-contaminated instruments could not be identified in 11 of 19 hospitals. In 12 of 15 hospitals with neurosurgical incidents, a decision was made to notify patients of their potential exposure. CONCLUSIONS Neurosurgical instruments used for treatment of patients with suspected or diagnosed CJD or patients whose diagnosis is unclear should be promptiy identified and sterilized using recommended CJD decontamination protocols. Inability to trace instruments complicates appropriate management of exposure incidents. The feasibility of instituting instrument tracking procedures should be considered. PMID:24225612

Three cases of Creutzfeldt-Jakob disease with prion protein gene codon180 mutation presenting with pathological laughing and crying.

PubMed

Iwasaki, Yasushi

2012-08-15

Although there are no reports of pathological laughing and crying being observed in patients with Creutzfeldt-Jakob disease (CJD), the author experienced three patients with CJD with prion protein gene codon180 mutation (V180I CJD) who showed this characteristic clinical finding. This finding was observed from the early disease stage in all 3 patients and continued for several months. Startle reaction was also remarkable in all patients, although myoclonus was generally mild. The dissociation between the startle reaction and myoclonus was suspected to be another feature of V180I CJD. The pathological laughing and crying co-occured with the startle reaction and stopped right before the onset of akinetic mutism, and the degree of both symptoms was almost parallel during this period. On the basis of MRI and autopsy findings, pathological laughing and crying was suspected of being induced by the widespread cerebral cortical involvement that is characteristic of V180I CJD. From the present observations, the author speculated that pathological laughing and crying may be a comparatively frequent observation in V180I CJD patients. Copyright © 2012 Elsevier B.V. All rights reserved.

MAD COW DISEASE: New Recruits for French Prion Research.

PubMed

Casassus, B

2000-12-01

As panic over "mad cow disease" engulfs France and threatens to spread to other countries in Western Europe, French research minister Roger-Gérard Schwartzenberg last week unveiled detailed plans for spending $27 million the government has earmarked for prion disease research in 2001. Next year's budget for studying prions--infectious, abnormal proteins linked to bovine spongiform encephalopathy and its human form, variant Creutzfeldt-Jakob disease--will triple France's current prion research spending.

Lithostathine quadruple-helical filaments form proteinase K-resistant deposits in Creutzfeldt-Jakob disease.

PubMed

Laurine, Emmanuelle; Grégoire, Catherine; Fändrich, Marcus; Engemann, Sabine; Marchal, Stéphane; Thion, Laurent; Mohr, Michel; Monsarrat, Bernard; Michel, Bernard; Dobson, Christopher M; Wanker, Erich; Erard, Monique; Verdier, Jean-Michel

2003-12-19

Autocatalytic cleavage of lithostathine leads to the formation of quadruple-helical fibrils (QHF-litho) that are present in Alzheimer's disease. Here we show that such fibrils also occur in Creutzfeldt-Jakob and Gerstmann-Sträussler-Scheinker diseases, where they form protease-K-resistant deposits and co-localize with amyloid plaques formed from prion protein. Lithostathine does not appear to change its native-like, globular structure during fibril formation. However, we obtained evidence that a cluster of six conserved tryptophans, positioned around a surface loop, could act as a mobile structural element that can be swapped between adjacent protein molecules, thereby enabling the formation of higher order fibril bundles. Despite their association with these clinical amyloid deposits, QHF-litho differ from typical amyloid fibrils in several ways, for example they produce a different infrared spectrum and cannot bind Congo Red, suggesting that they may not represent amyloid structures themselves. Instead, we suggest that lithostathine constitutes a novel component decorating disease-associated amyloid fibrils. Interestingly, [6,6']bibenzothiazolyl-2,2'-diamine, an agent found previously to disrupt aggregates of huntingtin associated with Huntington's disease, can dissociate lithostathine bundles into individual protofilaments. Disrupting QHF-litho fibrils could therefore represent a novel therapeutic strategy to combat clinical amyloidoses.

78 FR 11207 - Transmissible Spongiform Encephalopathies Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-02-15

... exposure to the variant Creutzfeldt-Jakob disease (vCJD) agent in Red Blood Cells for transfusion in the... days before the meeting. If FDA is unable to post the background material on its Web site prior to the... material is available at http://www.fda.gov/AdvisoryCommittees/Calendar/default.htm . Scroll down to the...

Singled out?

PubMed

Waller, Frank

2004-03-01

The increasing use of single use medical devices is being driven by a growing awareness of iatrogenic (from the Greek; caused by the doctor) and nosocomial infections. Public health perceptions relating to transmissible spongiform encephalopathies, specifically variant Creutzfeldt-Jakob disease (vCJD), the Human Immunodeficiency Virus (HIV) and Hepatitis B are high on the political agenda and a matter of concern to healthcare professionals.

77 FR 34390 - Draft Guidance for Industry: Amendment to “Guidance for Industry: Revised Preventive Measures To...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-11

... by Blood and Blood Products,'' Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice...CJD) by Blood and Blood Products'' dated May 2010 (2010 CJD/vCJD guidance). When finalized, the... Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products' '' dated April 2012. The draft...

R47H TREM2 variant increases risk of typical early-onset Alzheimer’s disease but not of prion or frontotemporal dementia

PubMed Central

CF, Slattery; J, Beck; L, Harper; G, Adamson; Z, Abdi; J, Uphill; T, Campbell; R, Druyeh; CJ, Mahoney; JD, Rohrer; J, Kenny; J, Lowe; KK, Leung; J, Barnes; SL, Clegg; M, Blair; JM, Nicholas; RJ, Guerreiro; JB, Rowe; C, Ponto; I, Zerr; H, Kretzschmar; P, Gambetti; SJ, Crutch; JD, Warren; MN, Rossor; NC, Fox; J, Collinge; JM, Schott; S, Mead

2015-01-01

Background Rare TREM2 variants are significant risk factors for Alzheimer’s disease. 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=13048) to determine whether TREM2 variants are risk factors or phenotypic modifiers in patients with Alzheimer’s disease (n=1002), frontotemporal dementia (n=358), sporadic (n=2500) and variant (n=115) Creutzfeldt-Jakob disease. Results We confirm only p.R47H as a risk factor for Alzheimer’s disease (OR=2.19; 95%CI=1.04-4.51; P=0.03). p.R47H does not significantly alter risk for frontotemporal dementia (OR=0.81), variant or sporadic Creutzfeldt-Jakob disease (OR=1.06 95%CI=0.66-1.69) in our cohorts. Individuals with p.R47H associated Alzheimer’s (n=12) had significantly earlier symptom onset than individuals with no TREM2 variants (n=551) (55.2years vs. 61.7years, P=0.02). We note that heterozygous p.R47H Alzheimer’s disease is memory led and otherwise indistinguishable from “typical” sporadic Alzheimer’s. Conclusion We find p.R47H is a risk factor for Alzheimer’s disease, but not frontotemporal dementia or prion disease. PMID:25160042

[A case of Creutzfeldt-Jakob in the Mexican north-east and review of current concepts on prion disease].

PubMed

Calderón-Garcidueñas, A L; Sagastegui-Rodríguez, J A; Canales-Ibarra, C; Farías-García, R

2001-01-01

The case reported here is that of a 50-year-old man from Saltillo, Coahuila, Mexico, who during the previous 15 months developed a demential syndrome and myoclonia. The brain biopsy led to establish a diagnosis of spongiform encephalopathy. The EEG showed periodic sharp wave complexes over the right hemisphere. A review on about prion diseases is included.

Creutzfeldt-Jakob disease lookback study: 21 years of surveillance for transfusion transmission risk.

PubMed

Crowder, Lauren A; Schonberger, Lawrence B; Dodd, Roger Y; Steele, Whitney R

2017-08-01

Transfusion transmission of human prion diseases has been observed for variant Creutzfeldt-Jakob disease (vCJD), but not for the classic forms of prion disease (CJD: sporadic, genetic, and iatrogenic). Although the presence of prions or misfolded prion proteins in blood has been documented in some patients with the most common form of CJD, sporadic CJD, no transfusion-transmitted cases of CJD have been recognized. Since 1995, the American Red Cross has conducted a lookback study of the recipients of blood products from donors who develop CJD to assess the risk of blood-borne CJD transmission in the United States. Blood donors subsequently diagnosed with confirmed or probable CJD were enrolled and the consignees were asked to identify the recipients of their blood products. These donors' transfusion recipients are traced annually with the National Death Index to see if they subsequently die of CJD. To date, 65 CJD donors have been enrolled along with 826 of their blood recipients. These recipients have contributed 3934 person-years of follow-up and no transfusion-transmitted cases of CJD have been recognized. From this study, as well as other epidemiologic studies, there is no evidence of CJD transfusion transmission; this risk remains theoretical. © 2017 AABB.

Guinea Pig Prion Protein Supports Rapid Propagation of Bovine Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease Prions.

PubMed

Watts, Joel C; Giles, Kurt; Saltzberg, Daniel J; Dugger, Brittany N; Patel, Smita; Oehler, Abby; Bhardwaj, Sumita; Sali, Andrej; Prusiner, Stanley B

2016-11-01

The biochemical and neuropathological properties of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) prions are faithfully maintained upon transmission to guinea pigs. However, primary and secondary transmissions of BSE and vCJD in guinea pigs result in long incubation periods of ∼450 and ∼350 days, respectively. To determine if the incubation periods of BSE and vCJD prions could be shortened, we generated transgenic (Tg) mice expressing guinea pig prion protein (GPPrP). Inoculation of Tg(GPPrP) mice with BSE and vCJD prions resulted in mean incubation periods of 210 and 199 days, respectively, which shortened to 137 and 122 days upon serial transmission. In contrast, three different isolates of sporadic CJD prions failed to transmit disease to Tg(GPPrP) mice. Many of the strain-specified biochemical and neuropathological properties of BSE and vCJD prions, including the presence of type 2 protease-resistant PrP Sc , were preserved upon propagation in Tg(GPPrP) mice. Structural modeling revealed that two residues near the N-terminal region of α-helix 1 in GPPrP might mediate its susceptibility to BSE and vCJD prions. Our results demonstrate that expression of GPPrP in Tg mice supports the rapid propagation of BSE and vCJD prions and suggest that Tg(GPPrP) mice may serve as a useful paradigm for bioassaying these prion isolates. Variant Creutzfeldt-Jakob disease (vCJD) and bovine spongiform encephalopathy (BSE) prions are two of the prion strains most relevant to human health. However, propagating these strains in mice expressing human or bovine prion protein has been difficult because of prolonged incubation periods or inefficient transmission. Here, we show that transgenic mice expressing guinea pig prion protein are fully susceptible to vCJD and BSE prions but not to sporadic CJD prions. Our results suggest that the guinea pig prion protein is a better, more rapid substrate than either bovine or human prion protein for propagating BSE and vCJD prions. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Altered Mitochondria, Protein Synthesis Machinery, and Purine Metabolism Are Molecular Contributors to the Pathogenesis of Creutzfeldt-Jakob Disease.

PubMed

Ansoleaga, Belén; Garcia-Esparcia, Paula; Llorens, Franc; Hernández-Ortega, Karina; Carmona Tech, Margarita; Antonio Del Rio, José; Zerr, Inga; Ferrer, Isidro

2016-06-12

Neuron loss, synaptic decline, and spongiform change are the hallmarks of sporadic Creutzfeldt-Jakob disease (sCJD), and may be related to deficiencies in mitochondria, energy metabolism, and protein synthesis. To investigate these relationships, we determined the expression levels of genes encoding subunits of the 5 protein complexes of the electron transport chain, proteins involved in energy metabolism, nucleolar and ribosomal proteins, and enzymes of purine metabolism in frontal cortex samples from 15 cases of sCJD MM1 and age-matched controls. We also assessed the protein expression levels of subunits of the respiratory chain, initiation and elongation translation factors of protein synthesis, and localization of selected mitochondrial components. We identified marked, generalized alterations of mRNA and protein expression of most subunits of all 5 mitochondrial respiratory chain complexes in sCJD cases. Expression of molecules involved in protein synthesis and purine metabolism were also altered in sCJD. These findings point to altered mRNA and protein expression of components of mitochondria, protein synthesis machinery, and purine metabolism as components of the pathogenesis of CJD. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

Cows for fear: is BSE a threat to human health? Bovine spongiform encephalopathy.

PubMed Central

Josephson, J

1998-01-01

In 1996, a new variant of Creutzfeldt-Jakob disease (vCJD)-a disease that causes lack of coordination, muscle twitching or jerking, dementia, and, eventually, death-suddenly appeared in Great Britain. It is believed that the victims contracted the disease from eating the beef of cattle stricken with bovine spongiform encephalopathy (BSE), or mad cow disease. As of December 1997, at least 25 people in the United Kingdom and France have contracted vCJD. PMID:9485478

Co-existence of Distinct Prion Types Enables Conformational Evolution of Human PrPSc by Competitive Selection*

PubMed Central

Haldiman, Tracy; Kim, Chae; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Qing, Liuting; Cohen, Mark L.; Langeveld, Jan; Telling, Glenn C.; Kong, Qingzhong; Safar, Jiri G.

2013-01-01

The unique phenotypic characteristics of mammalian prions are thought to be encoded in the conformation of pathogenic prion proteins (PrPSc). The molecular mechanism responsible for the adaptation, mutation, and evolution of prions observed in cloned cells and upon crossing the species barrier remains unsolved. Using biophysical techniques and conformation-dependent immunoassays in tandem, we isolated two distinct populations of PrPSc particles with different conformational stabilities and aggregate sizes, which frequently co-exist in the most common human prion disease, sporadic Creutzfeldt-Jakob disease. The protein misfolding cyclic amplification replicates each of the PrPSc particle types independently and leads to the competitive selection of those with lower initial conformational stability. In serial propagation with a nonglycosylated mutant PrPC substrate, the dominant PrPSc conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to its lowest stability. Cumulatively, the data show that sporadic Creutzfeldt-Jakob disease PrPSc is not a single conformational entity but a dynamic collection of two distinct populations of particles. This implies the co-existence of different prions, whose adaptation and evolution are governed by the selection of progressively less stable, faster replicating PrPSc conformers. PMID:23974118

Putaminal volume and diffusion in early familial Creutzfeldt-Jakob disease.

PubMed

Seror, Ilana; Lee, Hedok; Cohen, Oren S; Hoffmann, Chen; Prohovnik, Isak

2010-01-15

The putamen is centrally implicated in the pathophysiology of Creutzfeldt-Jakob Disease (CJD). To our knowledge, its volume has never been measured in this disease. We investigated whether gross putaminal atrophy can be detected by MRI in early stages, when the diffusion is already reduced. Twelve familial CJD patients with the E200K mutation and 22 healthy controls underwent structural and diffusion MRI scans. The putamen was identified in anatomical scans by two methods: manual tracing by a blinded investigator, and automatic parcellation by a computerized segmentation procedure (FSL FIRST). For each method, volume and mean Apparent Diffusion Coefficient (ADC) were calculated. ADC was significantly lower in CJD patients (697+/-64 microm(2)/s vs. 750+/-31 microm(2)/s, p<0.005), as expected, but the volume was not reduced. The computerized FIRST delineation yielded comparable ADC values to the manual method, but computerized volumes were smaller than manual tracing values. We conclude that significant diffusion reduction in the putamen can be detected by delineating the structure manually or with a computerized algorithm. Our findings confirm and extend previous voxel-based and observational studies. Putaminal volume was not reduced in our early-stage patients, thus confirming that diffusion abnormalities precede detectible atrophy in this structure.

[Doctor Francoise Cathala and history of prions diseases].

PubMed

Court, L; Hauw, J-J

2015-12-01

Doctor Françoise Cathala Pagesy, MD, MS, born on July 7, 1921 in Paris, passed away peacefully at home on November 5, 2012. Unconventional, passionate and enthusiastic neurologist and virologist, she devoted her life to research on latent and slow viral infections, specializing mainly on unconventional transmissible agents or prions. As a research member of Inserm (French Institute for Medical Research), she soon joined the team of Carlton Gajdusek (the NINCDS - National Institute of Nervous Central System and Stroke - of NIH), who first demonstrated the transmissibility of kuru and Creutzfeldt-Jakob disease to monkeys. When she came back to Paris, where she was followed by one of NIH members, Paul Brown, she joined the Centre de Recherches du Service de Santé des Armées (Army Health Research Center), in Percy-Clamart, where she found the experimental design and the attentive help needed for her research, which appeared heretical to many French virologists, including some authorities. A large number of research programs were set up with numerous collaborations involving CEA (Center for Atomic Energy) and other institutions in Paris and Marseilles on epidemiology, results of tissue inoculation, electrophysiology and neuropathology of human and animal prions diseases, and resistance of the infectious agent. International symposia were set up, where met, in the Val-de-Grâce hospital in Paris, the research community on "slow viral diseases". Stanley Prusiner introduced the concept - then badly accepted and still in evolution - of prion, a protein only infectious agent. Before retiring from Inserm, Françoise Cathala predicted and was involved in some of the huge sanitary crises in France. These were, first, Creutzfeldt-Jakob disease from contaminated growth hormone extracted from cadavers, which led parents to instigate legal procedure - a quite unusual practice in France. The second was Mad cow disease in the United Kingdom then in France, followed by new variant of Creutzfeldt-Jakob human epidemics, paradigmatic food safety crisis bringing together the poles of production (beef and meat-and-bone meal) and consumption, and leading to an unexpected social bang. Through Françoise Cathala exemplary life, the history of French, and more generally of worldwide prions diseases is dealt with. Copyright © 2014. Published by Elsevier Masson SAS.

Genetic and Transcriptomic Profiles of Inflammation in Neurodegenerative Diseases: Alzheimer, Parkinson, Creutzfeldt-Jakob and Tauopathies.

PubMed

López González, Irene; Garcia-Esparcia, Paula; Llorens, Franc; Ferrer, Isidre

2016-02-04

Polymorphisms in certain inflammatory-related genes have been identified as putative differential risk factors of neurodegenerative diseases with abnormal protein aggregates, such as sporadic Alzheimer's disease (AD) and sporadic Parkinson's disease (sPD). Gene expression studies of cytokines and mediators of the immune response have been made in post-mortem human brain samples in AD, sPD, sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2, Pick's disease (PiD), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration linked to mutation P301L in MAPT Frontotemporal lobar degeneration-tau (FTLD-tau). The studies have disclosed variable gene regulation which is: (1) disease-dependent in the frontal cortex area 8 in AD, sPD, sCJD MM1 and VV2, PiD, PSP and FTLD-tau; (2) region-dependent as seen when comparing the entorhinal cortex, orbitofrontal cortex, and frontal cortex area 8 (FC) in AD; the substantia nigra, putamen, FC, and angular gyrus in PD, as well as the FC and cerebellum in sCJD; (3) genotype-dependent as seen considering sCJD MM1 and VV2; and (4) stage-dependent as seen in AD at different stages of disease progression. These observations show that regulation of inflammation is much more complicated and diverse than currently understood, and that new therapeutic approaches must be designed in order to selectively act on specific targets in particular diseases and at different time points of disease progression.

Genetic and Transcriptomic Profiles of Inflammation in Neurodegenerative Diseases: Alzheimer, Parkinson, Creutzfeldt-Jakob and Tauopathies

PubMed Central

López González, Irene; Garcia-Esparcia, Paula; Llorens, Franc; Ferrer, Isidre

2016-01-01

Polymorphisms in certain inflammatory-related genes have been identified as putative differential risk factors of neurodegenerative diseases with abnormal protein aggregates, such as sporadic Alzheimer’s disease (AD) and sporadic Parkinson’s disease (sPD). Gene expression studies of cytokines and mediators of the immune response have been made in post-mortem human brain samples in AD, sPD, sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2, Pick’s disease (PiD), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration linked to mutation P301L in MAPT Frontotemporal lobar degeneration-tau (FTLD-tau). The studies have disclosed variable gene regulation which is: (1) disease-dependent in the frontal cortex area 8 in AD, sPD, sCJD MM1 and VV2, PiD, PSP and FTLD-tau; (2) region-dependent as seen when comparing the entorhinal cortex, orbitofrontal cortex, and frontal cortex area 8 (FC) in AD; the substantia nigra, putamen, FC, and angular gyrus in PD, as well as the FC and cerebellum in sCJD; (3) genotype-dependent as seen considering sCJD MM1 and VV2; and (4) stage-dependent as seen in AD at different stages of disease progression. These observations show that regulation of inflammation is much more complicated and diverse than currently understood, and that new therapeutic approaches must be designed in order to selectively act on specific targets in particular diseases and at different time points of disease progression. PMID:26861289

Creutzfeldt-Jakob Disease as a Cause of Cognitive Decline and Seizures in the Elderly: Diagnostic Pointers and Strategy for Investigation

PubMed Central

Williams, R.; Cresswell, F.; McClure, M.; Lane, R.

2011-01-01

Cognitive decline affects one in twenty people over the age of 65. There is often a paucity of clues as to the underlying pathology, and while the diagnosis will usually prove to be either Alzheimer's disease or vascular dementia, there may be clinical features suggesting rarer alternatives. This case of a 71-year-old lady with a 3-month history of progressive cognitive decline illustrates clinical features suggestive of Creutzfeltd-Jakob disease such as rapid decline in conscious level and myoclonic jerking. Diagnosis was confirmed by 3 means: (1) Electroencephalogram demonstrating periodic sharp wave complexes, (2) MRI brain showing cortical ribboning and high signal in the caudate nucleus, and (3) presence of protein S100 and protein14-3-3 in the cerebrospinal fluid. Postmortem brain histology confirmed a typical spongiform encephalopathy. Establishing an underlying aetiology is dementia is important not only for prognostic reasons but in order to detect potentially reversible causes. In cases of an atypical dementing illness our proposed investigations may assist in confirming or excluding underlying Creutzfeltd-Jakob disease. PMID:22194754

Wernicke-Korsakoff syndrome as a rare phenotype of sporadic Creutzfeldt-Jakob disease.

PubMed

Bielewicz, Joanna; Szczepańska-Szerej, Anna; Ogórek, Magdalena; Dropko, Piotr; Wojtal, Katarzyna; Rejdak, Konrad

2018-03-04

We reported the case of a patient with Wernicke-Korsakoff syndrome (WKs) as an early clinical manifestation of sporadic Creutzfeld-Jakob disease (sCJD). The 66-year-old female complained of dizziness and imbalance which mostly occurred while walking. A neurological examination revealed a triad of symptoms characteristic for WKs such as gaze paresis, ataxia of limbs and trunk as well as memory disturbances with confabulations. The disturbances increased during the course of the disease, which led to the death of the patient four months after the appearance of the signs. The patient was finally diagnosed with sCJD disease. The most useful ancillary examination results supporting sCJD diagnosis were brain diffusion DWI MRI (diffusion weighted magnetic resonance imaging) and the presence of 14-3-3 protein in CSF (cerebrospinal fluid). Since that manifestation of sCJD is very unique other causes should be taken into consideration while making a final diagnosis.

The CJD Neurological Status Scale: A New Tool for Evaluation of Disease Severity and Progression in Creutzfeldt - Jakob disease

PubMed Central

Cohen, Oren S.; Prohovnik, Isak; Korczyn, Amos D.; Ephraty, Lilach; Nitsan, Zeev; Tsabari, Rakefet; Appel, Shmuel; Rosenmann, Hanna; Kahana, Ester; Chapman, Joab

2011-01-01

Objectives To develop a scale sensitive for the neurological manifestations of Creutzfeldt-Jakob disease (CJD). Methods A 26-item CJD neurological status scale (CJD-NS) was created based on characteristic disease manifestations. Each sign was assigned to one of eight neurological systems to calculate a total scale score (TSS) and a system involvement score (SIS). The scale was administered to 37 CJD patients, 101 healthy first-degree relatives of the patients and 14 elderly patients with Parkinson's disease (PD). Results The mean TSS (±SD) was significantly higher in patients with CJD (13.19±5.63) compared to normal controls (0.41±0.78) and PD patients (9.71±3.05). The mean SIS was also significantly different between the CJD (5.19±1.22) and PD (2.78±1.18 p<0.01) groups reflecting the disseminated nature of neurological involvement in CJD. Using a cutoff of TSS>4 yielded a sensitivity of 97% for CJD, and specificity of 100% against healthy controls. All individual items showed excellent specificity against healthy subjects, but sensitivity was highly variable. Repeat assessments of CJD patients over 3-9 months revealed a time-dependent increase of both the TSS and the SIS reflecting the scale's ability to track disease progression. Conclusions The CJD-NS scale is sensitive to neurological signs and their progression in CJD patients. PMID:21303352

A prion primer

PubMed Central

Cashman, N R

1997-01-01

By biological and medical criteria, prions are infectious agents; however, many of their properties differ profoundly from those of conventional microbes. Prions are "encoded" by alterations in protein conformation rather than in nucleic acid or amino acid sequence. New epidemic prion diseases (bovine spongiform encephalopathy and new variant Creutzfeldt-Jakob disease) have recently emerged under the active surveillance of the modern world. The risk of contracting prion disease from blood products or other biologicals is now a focus of worldwide concern. Much has been discovered about prions and prion diseases, but much remains to be done. PMID:9371069

Ethical issues in human prion diseases.

PubMed

Tabrizi, S J; Elliott, C L; Weissmann, C

2003-01-01

Prion diseases or transmissible spongiform encephalopathies are a group of closely related transmissible neurodegenerative conditions of humans and animals, all of which are incurable. In recent years, they have captured public attention with the emergence of the bovine spongiform encephalopathy (BSE) epidemic in Europe, and more recently with the appearance of variant CJD (vCJD) in humans, a novel form of Creutzfeldt-Jakob disease (CJD) that is linked to dietary exposure to BSE. In this chapter, we outline ethical questions posed by research, diagnostic procedures and therapy in the field of prion diseases.

Creutzfeldt-Jakob Disease Presenting With Dizziness and Gaze-Evoked Nystagmus: A Case Report.

PubMed

Choi, Yun-Ju; Kang, Kyung-Wook; Lee, Sae-Young; Kang, Seung-Ho; Lee, Seung-Han; Kim, Byeong C

2016-02-01

Sporadic Creutzfeldt-Jakob disease (CJD) is clinically characterized by rapidly progressive dementia combined with other cardinal symptoms, such as myoclonus, visual or cerebellar disturbances, extrapyramidal or pyramidal disturbance, and akinetic mutism. However, as an initial manifestation, focal neurologic deficits other than the aforementioned or nonspecific generalized symptoms may lead to a misdiagnosis or a delayed diagnosis. The authors report a case of 66-year-old male patient with sporadic CJD who had dizziness, gaze-evoked nystagmus (GEN), and other central eye signs (impaired smooth pursuit, saccadic dysmetria) as an initial manifestation without dementia. The central eye signs led us to perform brain magnetic resonance images, which showed abnormal cortical high-signal intensity in both the cerebral and cerebellar hemispheres including the vestibulocerebellum. We reached a presumptive diagnosis of CJD, but the findings did not meet diagnostic criteria for probable CJD at that time. Three weeks after the initial work-ups, the patient presented with typical neurological findings of CJD: rapidly progressive dementia, akinetic mutism, and myoclonus of the left arm. Cerebrospinal fluid was positive for 14-3-3 protein, and electroencephalography showed periodic sharp wave complexes. In this patient, GEN and other central eye signs provided diagnostic clues for CJD. These unusual neurological manifestations may help physicians have a thorough knowledge of early deficits of CJD.

Intracranial Procedures and Expected Frequency of Creutzfeldt-Jakob Disease.

PubMed

Abrams, Joseph Y; Maddox, Ryan A; Schonberger, Lawrence B; Belay, Ermias D

2016-01-01

To assess the frequency and characteristics of intracranial procedures (ICPs) performed and the number of U.S. residents living with a history of ICP. These data are used to calculate the expected annual number of sporadic Creutzfeldt-Jakob disease (CJD) cases among U.S. residents with a history of ICP. The Nationwide Inpatient Sample provided data on the frequency and types of ICPs, and data from the National Center for Health Statistics was used to produce age-adjusted mortality rates. A model was constructed, which estimated long-term survival and sporadic CJD rates among ICP patients based on procedure type and age. There were an estimated 2,070,488 ICPs in the United States from 1998 to 2007, an average of over 200,000 per year. There were an estimated 2,023,726 U.S. residents in 2013 with a history of ICP in the previous 30 years. In 2013, there was expected to be 4.1 sporadic CJD cases (95% CI 1-8) among people with a history of ICP in the past 30 years. The considerable proportion of U.S. residents living with a history of ICP is important information for retrospective assessments of CJD or any other suspected long-term outcome of ICPs. © 2015 S. Karger AG, Basel.

The risk of transmitting prion disease by blood or plasma products.

PubMed

Knight, Richard

2010-12-01

Various experimental studies have shown infectivity in blood in relation to bovine spongiform encephalitis (BSE) and variant Creutzfeldt-Jakob disease (vCJD). Human to human transmission vCJD infection has been reported via transfusion of non-leukocyte-reduced red cells and, probably, via factor VIII concentrates. A number of precautionary measures are in place but uncertainties remain, especially concerning the number of BSE-infected people in the population. Additional measures such as prion filtration need consideration. Copyright © 2010 Elsevier Ltd. All rights reserved.

Risk of transmission of sporadic Creutzfeldt-Jakob disease by surgical procedures: systematic reviews and quality of evidence.

PubMed

López, Fernando J García; Ruiz-Tovar, María; Almazán-Isla, Javier; Alcalde-Cabero, Enrique; Calero, Miguel; de Pedro-Cuesta, Jesús

2017-10-01

Sporadic Creutzfeldt-Jakob disease (sCJD) is potentially transmissible to humans. This study aimed to summarise and rate the quality of the evidence of the association between surgery and sCJD. Firstly, we conducted systematic reviews and meta-analyses of case-control studies with major surgical procedures as exposures under study. To assess quality of evidence, we used the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Secondly, we conducted a systematic review of sCJD case reports after sharing neurosurgical instruments. Thirteen case-control studies met the inclusion criteria for the systematic review of case-control studies. sCJD was positively associated with heart surgery, heart and vascular surgery and eye surgery, negatively associated with tonsillectomy and appendectomy, and not associated with neurosurgery or unspecified major surgery. The overall quality of evidence was rated as very low. A single case-control study with a low risk of bias found a strong association between surgery conducted more than 20 years before disease onset and sCJD. Seven cases were described as potentially transmitted by reused neurosurgical instruments. The association between surgery and sCJD remains uncertain. Measures currently recommended for preventing sCJD transmission should be strongly maintained. Future studies should focus on the potential association between sCJD and surgery undergone a long time previously.

Sporadic Creutzfeldt-Jakob Disease in a Woman Married Into a Gerstmann-Sträussler-Scheinker Family: An Investigation of Prions Transmission via Microchimerism.

PubMed

Areškeviciute, Aušrine; Melchior, Linea Cecilie; Broholm, Helle; Krarup, Lars-Henrik; Granhøj Lindquist, Suzanne; Johansen, Peter; McKenzie, Neil; Green, Alison; Nielsen, Jørgen Erik; Laursen, Henning; Løbner Lund, Eva

2018-06-07

This is the first report of presumed sporadic Creutzfeldt-Jakob disease (sCJD) and Gerstmann-Sträussler-Scheinker disease (GSS) with the prion protein gene c.305C>T mutation (p.P102L) occurring in one family. The father and son were affected with GSS and the mother had a rapidly progressive form of CJD. Diagnosis of genetic, variant, and iatrogenic CJD was ruled out based on the mother's clinical history, genetic tests, and biochemical investigations, all of which supported the diagnosis of sCJD. However, given the low incidence of sCJD and GSS, their co-occurrence in one family is extraordinary and challenging. Thus, a hypothesis for the transmission of infectious prion proteins (PrPSc) via microchimerism was proposed and investigated. DNA from 15 different brain regions and plasma samples of the CJD patient was subjected to PCR and shallow sequencing for detection of a male sex-determining chromosome Y (chr. Y). However, no trace of chr. Y was found. A long CJD incubation period or presumed small concentrations of chr. Y may explain the obtained results. Further studies of CJD and GSS animal models with controlled genetic and proteomic features are needed to determine whether maternal CJD triggered via microchimerism by a GSS fetus might present a new PrPSc transmission route.

Detection of prions in blood from patients with variant Creutzfeldt-Jakob disease

PubMed Central

Concha-Marambio, Luis; Pritzkow, Sandra; Moda, Fabio; Tagliavini, Fabrizio; Ironside, James W.; Schulz, Paul E.; Soto, Claudio

2017-01-01

Human prion diseases are infectious and invariably fatal neurodegenerative diseases. They include sporadic Creutzfeldt-Jakob disease (sCJD), the most common form, and variant CJD (vCJD), which is caused by interspecies transmission of prions from cattle infected by bovine spongiform encephalopathy. Development of a biochemical assay for the sensitive, specific, early, and noninvasive detection of prions (PrPSc) in the blood of patients affected by prion disease is a top medical priority to increase the safety of the blood supply. vCJD has already been transmitted from human to human by blood transfusion, and the number of asymptomatic carriers of vCJD in the U.K. alone is estimated to be 1 in 2000 people. We used the protein misfolding cyclic amplification (PMCA) technique to analyze blood samples from 14 cases of vCJD and 153 controls, including patients affected by sCJD and other neurodegenerative or neurological disorders as well as healthy subjects. Our results showed that PrPSc could be detected with 100% sensitivity and specificity in blood samples from vCJD patients. Detection was possible in any of the blood fractions analyzed and could be done with as little as a few microliters of sample volume. The PrPSc concentration in blood was estimated to be ~0.5 pg/ml. Our findings suggest that PMCA may be useful for premortem noninvasive diagnosis of vCJD and to identify prion contamination of the blood supply. Further studies are needed to fully validate the technology. PMID:28003548

The Structure of Intrinsically Disordered Peptides Implicated in Amyloid Diseases: Insights from Fully Atomistic Simulations

NASA Astrophysics Data System (ADS)

Wu, Chun; Shea, Joan-Emma

Protein aggregation involves the self-assembly of proteins into large β-sheet-rich complexes. This process can be the result of aberrant protein folding and lead to "amyloidosis," a condition characterized by deposits of protein aggregates known as amyloids on various organs of the body [1]. Amyloid-related diseases include, among others, Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, and type II diabetes [2, 3, 4]. In other instances, however, protein aggregation is not a pathological process, but rather a functional one, with aggregates serving as structural scaffolds in a number of organisms [5].

Quantitative Risk Assessment of Bovine Spongiform Encephalopathy

NASA Astrophysics Data System (ADS)

Tsutsui, Toshiyuki; Kasuga, Fumiko

Bovine spongiform encephalopathy (BSE) is a progressive neurological disease of cattle affecting the central nervous system and was first diagnosed in the United Kingdom (UK) in 1986 (Wells et al., 1987). This disease is one of the transmissible spongiform encephalopathy (TSE) which includes Creutzfeldt-Jakob disease (CJD) in humans and scrapie in sheep. The causative agent of TSE is considered to be an abnormal form of prion protein. However, the details of its pathogenic mechanism have not been fully identified. Scrapie, which causes neurological symptoms in sheep and goats, has existed in the UK for 200 years (Hoinville, 1996) and spread across the rest of the world in the 1900s (Detwiler & Baylis, 2003). There has been no report so far that scrapie can be transmitted to humans. Initially, BSE was also considered as a disease affecting only animals. However, a variant type of Creutzfeldt-Jakob disease (vCJD) was first reported in the UK, and exposure to a BSE agent was suspected (Collinge, Sidle, Meads, Ironside, & Hill, 1996). vCJD is clinically and pathologically different from the sporadic type of CJD, and age at clinical onset of vCJD is younger than sporadic type (Will et al., 1996). Since the UK government announced the possible association between BSE and vCJD in 1996, BSE has become a huge public health concern all over the world. Of particular concern about vCJD, the fatal disease in younger age, distorted consumer confidence in beef safety, and as a result reduced beef consumption has been seen in many BSE-affected countries.

Heterozygous genotype at codon 129 correlates with prolonged disease course in Heidenhain variant sporadic CJD: case report.

PubMed

Townley, Ryan A; Dawson, Elliot T; Drubach, Daniel A

2018-02-01

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapid and fatal neurodegenerative disease defined by misfolded prion proteins accumulating in the brain. A minority of cases initially present with posterior cortical atrophy (PCA) phenotype, also known as Heidenhain variant or visual variant CJD. This case provides further evidence of sCJD presenting as PCA. The case also provides evidence for early DWI changes and cortical atrophy over 30 months before neurologic decline and subsequent death. The prolonged disease course correlates with prion protein codon 129 heterozygosity and coexistence of multiple prion strains.

The epidemics of bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: current status and future prospects.

PubMed Central

Smith, Peter G.

2003-01-01

The large epidemic of bovine spongiform encephalopathy (BSE) in the United Kingdom has been in decline since 1992, but has spread to other countries. The extensive control measures that have been put in place across the European Union and also in Switzerland should have brought the transmission of BSE under control in these countries, provided that the measures were properly enforced. Postmortem tests on brain tissue enable infected animals to be detected during the late stages of the incubation period, but tests that can be performed on live animals (including humans) and that will detect infections early are urgently needed. The number of infected animals currently entering the food chain is probably small, and the controls placed on bovine tissues in the European Union and Switzerland should ensure that any risks to human health are small and diminishing. Vigilance is required in all countries, especially in those in which there has been within-species recycling of ruminant feed. Fewer than 150 people, globally, have been diagnosed with variant Creutzfeldt-Jakob disease (vCJD), but there are many uncertainties about the future course of the epidemic because of the long and variable incubation period. Better control measures are necessary to guard against the possibility of iatrogenic transmission through blood transfusion or contaminated surgical instruments. These measures will required sensitive and specific, diagnostic tests and improved decontamination methods. PMID:12751420

Update: Dura Mater Graft-Associated Creutzfeldt-Jakob Disease - Japan, 1975-2017.

PubMed

Ae, Ryusuke; Hamaguchi, Tsuyoshi; Nakamura, Yosikazu; Yamada, Masahito; Tsukamoto, Tadashi; Mizusawa, Hidehiro; Belay, Ermias D; Schonberger, Lawrence B

2018-03-09

Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder that, according to the most well accepted hypothesis (1), is caused by replicating, transmissible, abnormal forms of a host-encoded prion protein (prions). Most CJD cases occur spontaneously (sporadic CJD) or are inherited (genetic CJD). Iatrogenic CJD can occur after exposure to prion-contaminated instruments or products in medical/surgical settings. Cadaveric dura mater graft-associated CJD (dCJD) accounts for a common form of iatrogenic CJD. This report summarizes the epidemiologic features of 154 cases of dCJD identified in Japan during 1975-2017; these cases account for >60% of dCJD cases reported worldwide (1,2). The unusually high prevalence of dCJD in Japan was first reported in 1997 (3). In 2008, a single brand of graft (Lyodura [B. Braun Melsungen AG, Melsungen, Germany]), frequently used as a patch in neurosurgical procedures, was identified as the probable vehicle of transmission (4). No international recall of the implicated Lyodura occurred, the product had a relatively long shelf life, and the grafts were used frequently in Japanese patients with non-life-threatening conditions (4,5). Since 2008, additional cases have been ascertained, reflecting the identification of previously missed cases and the occurrence of new cases with longer latency periods (interval from exposure to symptom onset) for dCJD (up to 30 years), underscoring the importance of maintaining surveillance for dCJD.

Altered Ca2+ homeostasis induces Calpain-Cathepsin axis activation in sporadic Creutzfeldt-Jakob disease.

PubMed

Llorens, Franc; Thüne, Katrin; Sikorska, Beata; Schmitz, Matthias; Tahir, Waqas; Fernández-Borges, Natalia; Cramm, Maria; Gotzmann, Nadine; Carmona, Margarita; Streichenberger, Nathalie; Michel, Uwe; Zafar, Saima; Schuetz, Anna-Lena; Rajput, Ashish; Andréoletti, Olivier; Bonn, Stefan; Fischer, Andre; Liberski, Pawel P; Torres, Juan Maria; Ferrer, Isidre; Zerr, Inga

2017-04-27

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent form of human prion disease and it is characterized by the presence of neuronal loss, spongiform degeneration, chronic inflammation and the accumulation of misfolded and pathogenic prion protein (PrP Sc ). The molecular mechanisms underlying these alterations are largely unknown, but the presence of intracellular neuronal calcium (Ca 2+ ) overload, a general feature in models of prion diseases, is suggested to play a key role in prion pathogenesis.Here we describe the presence of massive regulation of Ca 2+ responsive genes in sCJD brain tissue, accompanied by two Ca 2+ -dependent processes: endoplasmic reticulum stress and the activation of the cysteine proteases Calpains 1/2. Pathogenic Calpain proteins activation in sCJD is linked to the cleavage of their cellular substrates, impaired autophagy and lysosomal damage, which is partially reversed by Calpain inhibition in a cellular prion model. Additionally, Calpain 1 treatment enhances seeding activity of PrP Sc in a prion conversion assay. Neuronal lysosomal impairment caused by Calpain over activation leads to the release of the lysosomal protease Cathepsin S that in sCJD mainly localises in axons, although massive Cathepsin S overexpression is detected in microglial cells. Alterations in Ca 2+ homeostasis and activation of Calpain-Cathepsin axis already occur at pre-clinical stages of the disease as detected in a humanized sCJD mouse model.Altogether our work indicates that unbalanced Calpain-Cathepsin activation is a relevant contributor to the pathogenesis of sCJD at multiple molecular levels and a potential target for therapeutic intervention.

Region-specific protein misfolding cyclic amplification reproduces brain tropism of prion strains.

PubMed

Privat, Nicolas; Levavasseur, Etienne; Yildirim, Serfildan; Hannaoui, Samia; Brandel, Jean-Philippe; Laplanche, Jean-Louis; Béringue, Vincent; Seilhean, Danielle; Haïk, Stéphane

2017-10-06

Human prion diseases such as Creutzfeldt-Jakob disease are transmissible brain proteinopathies, characterized by the accumulation of a misfolded isoform of the host cellular prion protein (PrP) in the brain. According to the prion model, prions are defined as proteinaceous infectious particles composed solely of this abnormal isoform of PrP (PrP Sc ). Even in the absence of genetic material, various prion strains can be propagated in experimental models. They can be distinguished by the pattern of disease they produce and especially by the localization of PrP Sc deposits within the brain and the spongiform lesions they induce. The mechanisms involved in this strain-specific targeting of distinct brain regions still are a fundamental, unresolved question in prion research. To address this question, we exploited a prion conversion in vitro assay, protein misfolding cyclic amplification (PMCA), by using experimental scrapie and human prion strains as seeds and specific brain regions from mice and humans as substrates. We show here that region-specific PMCA in part reproduces the specific brain targeting observed in experimental, acquired, and sporadic Creutzfeldt-Jakob diseases. Furthermore, we provide evidence that, in addition to cellular prion protein, other region- and species-specific molecular factors influence the strain-dependent prion conversion process. This important step toward understanding prion strain propagation in the human brain may impact research on the molecular factors involved in protein misfolding and the development of ultrasensitive methods for diagnosing prion disease. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Deep Learning Representation from Electroencephalography of Early-Stage Creutzfeldt-Jakob Disease and Features for Differentiation from Rapidly Progressive Dementia.

PubMed

Morabito, Francesco Carlo; Campolo, Maurizio; Mammone, Nadia; Versaci, Mario; Franceschetti, Silvana; Tagliavini, Fabrizio; Sofia, Vito; Fatuzzo, Daniela; Gambardella, Antonio; Labate, Angelo; Mumoli, Laura; Tripodi, Giovanbattista Gaspare; Gasparini, Sara; Cianci, Vittoria; Sueri, Chiara; Ferlazzo, Edoardo; Aguglia, Umberto

2017-03-01

A novel technique of quantitative EEG for differentiating patients with early-stage Creutzfeldt-Jakob disease (CJD) from other forms of rapidly progressive dementia (RPD) is proposed. The discrimination is based on the extraction of suitable features from the time-frequency representation of the EEG signals through continuous wavelet transform (CWT). An average measure of complexity of the EEG signal obtained by permutation entropy (PE) is also included. The dimensionality of the feature space is reduced through a multilayer processing system based on the recently emerged deep learning (DL) concept. The DL processor includes a stacked auto-encoder, trained by unsupervised learning techniques, and a classifier whose parameters are determined in a supervised way by associating the known category labels to the reduced vector of high-level features generated by the previous processing blocks. The supervised learning step is carried out by using either support vector machines (SVM) or multilayer neural networks (MLP-NN). A subset of EEG from patients suffering from Alzheimer's Disease (AD) and healthy controls (HC) is considered for differentiating CJD patients. When fine-tuning the parameters of the global processing system by a supervised learning procedure, the proposed system is able to achieve an average accuracy of 89%, an average sensitivity of 92%, and an average specificity of 89% in differentiating CJD from RPD. Similar results are obtained for CJD versus AD and CJD versus HC.

Current and future molecular diagnostics for prion diseases.

PubMed

Lehto, Marty T; Peery, Harry E; Cashman, Neil R

2006-07-01

It is now widely held that the infectious agents underlying the transmissible spongiform encephalopathies are prions, which are primarily composed of a misfolded, protease-resistant isoform of the host prion protein. Untreatable prion disorders include some human diseases, such as Creutzfeldt-Jakob disease, and diseases of economically important animals, such as bovine spongiform encephalopathy (cattle) and chronic wasting disease (deer and elk). Detection and diagnosis of prion disease (and presymptomatic incubation) is contingent upon developing novel assays, which exploit properties uniquely possessed by this misfolded protein complex, rather than targeting an agent-specific nucleic acid. This review highlights some of the conventional and disruptive technologies developed to respond to this challenge.

Differential Diagnosis of Jakob-Creutzfeldt Disease

PubMed Central

Paterson, Ross W.; Torres-Chae, Charles C.; Kuo, Amy L.; Ando, Tim; Nguyen, Elizabeth A.; Wong, Katherine; DeArmond, Stephen J.; Haman, Aissa; Garcia, Paul; Johnson, David Y.; Miller, Bruce L.; Geschwind, Michael D.

2015-01-01

Objectives To identify the misdiagnoses of patients with sporadic Jakob-Creutzfeldt disease (sCJD) during the course of their disease and determine which medical specialties saw patients with sCJD prior to the correct diagnosis being made and at what point in the disease course a correct diagnosis was made. Design Retrospective medical record review. Setting A specialty referral center of a tertiary academic medical center. Participants One hundred sixty-three serial patients over a 5.5-year period who ultimately had pathologically proven sCJD. The study used the subset of 97 patients for whom we had adequate medical records. Main Outcome Measures Other diagnoses considered in the differential diagnosis and types of medical specialties assessing patients with sCJD. Results Ninety-seven subjects’ records were used in the final analysis. The most common disease categories of misdiagnosis were neurodegenerative, autoimmune/paraneoplastic, infectious, and toxic/metabolic disorders. The most common individual misdiagnoses were viral encephalitis, paraneoplastic disorder, depression, vertigo, Alzheimer disease, stroke, unspecified dementia, central nervous system vasculitis, peripheral neuropathy, and Hashimoto encephalopathy. The physicians who most commonly made these misdiagnoses were primary care physicians and neurologists; in the 18% of patients who were diagnosed correctly at their first assessment, the diagnosis was almost always by a neurologist. The mean time from onset to diagnosis was 7.9 months, an average of two-thirds of the way through their disease course. Conclusions Diagnosis of sCJD is quite delayed. When evaluating patients with rapidly progressive dementia with suspected neurodegenerative, autoimmune, infectious, or toxic/metabolic etiology, sCJD should also be included in the differential diagnosis, and appropriate diagnostic tests, such as diffusion brain magnetic resonance imaging, should be considered. Primary care physicians and neurologists need improved training in sCJD diagnosis. PMID:23229042

Validation of α-Synuclein as a CSF Biomarker for Sporadic Creutzfeldt-Jakob Disease.

PubMed

Llorens, Franc; Kruse, Niels; Karch, André; Schmitz, Matthias; Zafar, Saima; Gotzmann, Nadine; Sun, Ting; Köchy, Silja; Knipper, Tobias; Cramm, Maria; Golanska, Ewa; Sikorska, Beata; Liberski, Pawel P; Sánchez-Valle, Raquel; Fischer, Andre; Mollenhauer, Brit; Zerr, Inga

2018-03-01

The analysis of cerebrospinal fluid (CSF) biomarkers gains importance in the differential diagnosis of prion diseases. However, no single diagnostic tool or combination of them can unequivocally confirm prion disease diagnosis. Electrochemiluminescence (ECL)-based immunoassays have demonstrated to achieve high diagnostic accuracy in a variety of sample types due to their high sensitivity and dynamic range. Quantification of CSF α-synuclein (a-syn) by an in-house ECL-based ELISA assay has been recently reported as an excellent approach for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD), the most prevalent form of human prion disease. In the present study, we validated a commercially available ECL-based a-syn ELISA platform as a diagnostic test for correct classification of sCJD cases. CSF a-syn was analysed in 203 sCJD cases with definite diagnosis and in 445 non-CJD cases. We investigated reproducibility and stability of CSF a-syn and made recommendations for its analysis in the sCJD diagnostic workup. A sensitivity of 98% and a specificity of 97% were achieved when using an optimal cut-off of 820 pg/mL a-syn. Moreover, we were able to show a negative correlation between a-syn levels and disease duration suggesting that CSF a-syn may be a good prognostic marker for sCJD patients. The present study validates the use of a-syn as a CSF biomarker of sCJD and establishes the clinical and pre-analytical parameters for its use in differential diagnosis in clinical routine. Additionally, the current test presents some advantages compared to other diagnostic approaches: it is fast, economic, requires minimal amount of CSF and a-syn levels are stable along disease progression.

Somatic mosaicism in a case of apparently sporadic Creutzfeldt-Jakob disease carrying a de novo D178N mutation in the PRNP gene.

PubMed

Alzualde, A; Moreno, F; Martínez-Lage, P; Ferrer, I; Gorostidi, A; Otaegui, D; Blázquez, L; Atares, B; Cardoso, S; Martínez de Pancorbo, M; Juste, R; Rodríguez-Martínez, A B; Indakoetxea, B; López de Munain, A

2010-10-05

Transmissible spongiform encephalopathies (TSEs) are a group of rare fatal neurodegenerative disorders. Creutzfeldt-Jakob disease (CJD) represents the most common form of TSE and can be classified into sporadic, genetic, iatrogenic and variant forms. Genetic cases are related to prion protein gene mutations but they only account for 10-20% of cases. Here we report an apparently sporadic CJD case with negative family history carrying a mutation at codon 178 of prion protein gene. This mutation is a de novo mutation as the parents of the case do not show it. Furthermore the presence of three different alleles (wild type 129M-178D and 129V-178D and mutated 129V-178N), confirmed by different methods, indicates that this de novo mutation is a post-zygotic mutation that produces somatic mosaicism. The proportion of mutated cells in peripheral blood cells and in brain tissue was similar and was estimated at approximately 97%, suggesting that the mutation occurred at an early stage of embryogenesis. Neuropathological examination disclosed spongiform change mainly involving the caudate and putamen, and the cerebral cortex, together with proteinase K-resistant PrP globular deposits in the cerebrum and cerebellum. PrP typing was characterized by a lower band of 21 kDa. This is the first case of mosaicism described in prion diseases and illustrates a potential etiology for apparently sporadic neurodegenerative diseases. In light of this case, genetic counseling for inherited and sporadic forms of transmissible encephalopathies should take into account this possibility for genetic screening procedures.

Early pathology in sleep studies of patients with familial Creutzfeldt-Jakob disease.

PubMed

Givaty, Gili; Maggio, Nicola; Cohen, Oren S; Blatt, Ilan; Chapman, Joab

2016-10-01

In this study, we aimed to assess sleep function in patients with recent-onset familial Creutzfeldt-Jakob disease (fCJD). The largest cluster of fCJD patients is found in Jews of Libyan origin, linked to the prion protein gene (PRNP) E200K mutation. The high index of suspicion in these patients often leads to early diagnosis, with complaints of insomnia being a very common presenting symptom of the disease. The study included 10 fCJD patients diagnosed by clinical manifestations, magnetic resonance imaging (MRI) scan of the brain, elevated tau protein in the cerebrospinal fluid (CSF) and positive PRNP E200K mutation. Standard polysomnography was performed after a brief interview confirming the presence of sleep disturbances. All patients showed a pathological sleep pattern according to all scoring evaluation settings. The sleep stages were characterized by (i) disappearance of sleep spindles; (ii) outbursts of periodic sharp waves and shallowing of sleep consisting in increased Stage 2 and wake periods during the night, as well as decrease of slow-wave sleep and rapid eye movement (REM) sleep. Recordings of respiratory functions reported irregular breathing with central and obstructive apnea and hypopnea. The typical hypotonia occurring during the night and atonia during REM sleep were replaced by hyperactive sleep consisting of multiple jerks, movements and parasomnia (mainly talking) throughout the night. In conclusion, we report unique pathological sleep patterns in early fCJD associated with the E200K mutation. Specific respiratory disturbances and lack of atonia could possibly serve as new, early diagnostic tools in the disease. © 2016 European Sleep Research Society.

The risk of bovine spongiform encephalopathy ('mad cow disease') to human health.

PubMed

Brown, P

1997-09-24

Some human cases of the transmissible neurodegenerative disorder Creutzfeldt-Jakob disease recently seen in Great Britain are thought to have resulted from eating beef infected with the agent of bovine spongiform encephalopathy. Reasons for and against this presumption are explained, and the question of a similar situation occurring in countries other than Britain-in particular, the United States-is discussed in terms of the existence of scrapie (in sheep) or unrecognized bovine spongiform encephalopathy (in cattle), the practice of recycling nonedible sheep and cattle tissue for animal nutrition, and precautionary measures already taken or under consideration by government agencies

Detection and partial discrimination of atypical and classical bovine spongiform encephalopathies in cattle and primates using real-time quaking-induced conversion assay.

PubMed

Levavasseur, Etienne; Biacabe, Anne-Gaëlle; Comoy, Emmanuel; Culeux, Audrey; Grznarova, Katarina; Privat, Nicolas; Simoneau, Steve; Flan, Benoit; Sazdovitch, Véronique; Seilhean, Danielle; Baron, Thierry; Haïk, Stéphane

2017-01-01

The transmission of classical bovine spongiform encephalopathy (C-BSE) through contaminated meat product consumption is responsible for variant Creutzfeldt-Jakob disease (vCJD) in humans. More recent and atypical forms of BSE (L-BSE and H-BSE) have been identified in cattle since the C-BSE epidemic. Their low incidence and advanced age of onset are compatible with a sporadic origin, as are most cases of Creutzfeldt-Jakob disease (CJD) in humans. Transmissions studies in primates and transgenic mice expressing a human prion protein (PrP) indicated that atypical forms of BSE may be associated with a higher zoonotic potential than classical BSE, and require particular attention for public health. Recently, methods designed to amplify misfolded forms of PrP have emerged as promising tools to detect prion strains and to study their diversity. Here, we validated real-time quaking-induced conversion assay for the discrimination of atypical and classical BSE strains using a large series of bovine samples encompassing all the atypical BSE cases detected by the French Centre of Reference during 10 years of exhaustive active surveillance. We obtained a 100% sensitivity and specificity for atypical BSE detection. In addition, the assay was able to discriminate atypical and classical BSE in non-human primates, and also sporadic CJD and vCJD in humans. The RT-QuIC assay appears as a practical means for a reliable detection of atypical BSE strains in a homologous or heterologous PrP context.

Survival and re-operation rates after neurosurgical procedures in Scotland: implications for targeted surveillance of sub-clinical variant Creutzfeldt-Jakob disease.

PubMed

Bird, Sheila M; Merrall, Elizabeth L C; Ward, Hester J T; Will, Robert G

2009-01-01

To assess the feasibility of post-mortem surveillance for subclinical variant Creutzfeldt-Jakob disease (vCJD) at least 5 years after neurosurgical procedures. Using Scottish record linkage, we estimated 5-year survival and re-operation rates after 4 neurosurgical procedures performed during 1993-2001 and identified as high or medium risk for transmitting vCJD: [B] drainage of extra- or subdural haematoma, [E] primary or revisional decompression operations and [H] creation of other ventricular shunts were classified as high risk; [C] operations on cerebral aneurysm (clipping) were classified as medium risk. Fatality rate at 1 year depended strongly on procedure, weakly or not at all on sex and era, and increased with age. Procedure rates differed by sex. The rate of subsequent neurosurgical operations was highest for procedure [H] (sole: 21%; multiple: 28%). Each year, the UK has a new cohort of some 5,000 5-year survivors after a high- or medium-risk neurosurgical procedure, whose subsequent annual mortality is at least 3%. Even if half the surviving 5-year survivors of neurosurgery since 1996 gave consent-in-life for vCJD-informative testing at post-mortem, there would be too few relevant post-mortems in 2008-2010 (around 1,600) for 'nil detections' to exclude a 1 in 1,000 subclinical vCJD rate. Autopsy surveillance beyond 2010, or among 5-year survivors of non-neurosurgical at-risk operations, would be needed. (c) 2009 S. Karger AG, Basel.

Transmission of sporadic Creutzfeldt-Jakob disease by blood transfusion: risk factor or possible biases.

PubMed

Puopolo, Maria; Ladogana, Anna; Vetrugno, Vito; Pocchiari, Maurizio

2011-07-01

The occurrence of transfusion transmissions of variant Creutzfeldt-Jakob disease (CJD) cases has reawakened attention to the possible similar risk posed by other forms of CJD. CJD with a definite or probable diagnosis (sporadic CJD, n = 741; genetic CJD, n = 175) and no-CJD patients with definite alternative diagnosis (n = 482) with available blood transfusion history were included in the study. The risk of exposure to blood transfusion occurring more than 10 years before disease onset and for some possible confounding factors was evaluated by calculating crude odds ratios (ORs). Variables with significant ORs in univariate analyses were included in multivariate logistic regression analyses. In the univariate model, blood transfusion occurring more than 10 years before clinical onset is 4.1-fold more frequent in sporadic CJD than in other neurologic disorders. This significance is lost when the 10-year lag time was not considered. Multivariate analyses show that the risk of developing sporadic CJD after transfusion increases (OR, 5.05) after adjusting for possible confounding factors. Analysis conducted on patients with genetic CJD did not reveal any significant risk factor associated with transfusion. This is the first case-control study showing a significant risk of transfusion occurring more than 10 years before clinical onset in sporadic CJD patients. It remains questionable whether the significance of these data is biologically plausible or the consequence of biases in the design of the study, but they counterbalance previous epidemiologic negative reports that might have overestimated the assessment of blood safety in sporadic CJD. © 2010 American Association of Blood Banks.

Prion Diseases: Update on Mad Cow Disease, Variant Creutzfeldt-Jakob Disease, and the Transmissible Spongiform Encephalopathies.

PubMed

Janka, Jacqueline; Maldarelli, Frank

2004-08-01

Transmissible spongiform encephalopathies (TSEs) are a group of progressive, fatal neurodegenerative disorders that share a common spongiform histopathology. TSEs may be transmitted in a sporadic, familial, iatrogenic, or zoonotic fashion. The putative infectious agent of TSE, the prion, represents a novel paradigm of infectious disease with disease transmission in the absence of nucleic acid. Several small but spectacular epidemics of TSEs in man have prompted widespread public health and food safety concerns. Although TSEs affect a comparatively small number of individuals, prion research has revealed fascinating insights of direct relevance to common illnesses. This paper reviews recent advances that have shed new light on the nature of prions and TSEs.

Medicinal and other products and human and animal transmissible spongiform encephalopathies: memorandum from a WHO meeting.

PubMed Central

1997-01-01

The report in March 1996 of 10 human cases of a novel from of Creutzfeldt-Jakob disease in the United Kingdom, and its possible link to the agent that causes bovine spongiform encephalopathy (BSE), raises many questions about the safety of animal-derived products and by-products entering the food chain or being used in medicine. This Memorandum updates the preventive measures put forward in 1991 to minimize the risks associated with the use of bovine-derived materials in medicinal products and medical devices. PMID:9509622

Regional and subtype-dependent miRNA signatures in sporadic Creutzfeldt-Jakob disease are accompanied by alterations in miRNA silencing machinery and biogenesis

PubMed Central

Kanata, Eirini; Dafou, Dimitra; Díaz-Lucena, Daniela; Vivancos, Ana; Shomroni, Orr; Zafar, Saima; Schmitz, Matthias; Fernández-Borges, Natalia; Andréoletti, Olivier; Díez, Juana; Fischer, Andre; Sklaviadis, Theodoros; Ferrer, Isidre; Zerr, Inga

2018-01-01

Increasing evidence indicates that microRNAs (miRNAs) are contributing factors to neurodegeneration. Alterations in miRNA signatures have been reported in several neurodegenerative dementias, but data in prion diseases are restricted to ex vivo and animal models. The present study identified significant miRNA expression pattern alterations in the frontal cortex and cerebellum of sporadic Creutzfeldt-Jakob disease (sCJD) patients. These changes display a highly regional and disease subtype-dependent regulation that correlates with brain pathology. We demonstrate that selected miRNAs are enriched in sCJD isolated Argonaute(Ago)-binding complexes in disease, indicating their incorporation into RNA-induced silencing complexes, and further suggesting their contribution to disease-associated gene expression changes. Alterations in the miRNA-mRNA regulatory machinery and perturbed levels of miRNA biogenesis key components in sCJD brain samples reported here further implicate miRNAs in sCJD gene expression (de)regulation. We also show that a subset of sCJD-altered miRNAs are commonly changed in Alzheimer’s disease, dementia with Lewy bodies and fatal familial insomnia, suggesting potential common mechanisms underlying these neurodegenerative processes. Additionally, we report no correlation between brain and cerebrospinal fluid (CSF) miRNA-profiles in sCJD, indicating that CSF-miRNA profiles do not faithfully mirror miRNA alterations detected in brain tissue of human prion diseases. Finally, utilizing a sCJD MM1 mouse model, we analyzed the miRNA deregulation patterns observed in sCJD in a temporal manner. While fourteen sCJD-related miRNAs were validated at clinical stages, only two of those were changed at early symptomatic phase, suggesting that the miRNAs altered in sCJD may contribute to later pathogenic processes. Altogether, the present work identifies alterations in the miRNA network, biogenesis and miRNA-mRNA silencing machinery in sCJD, whereby contributions to disease mechanisms deserve further investigation. PMID:29357384

Regional and subtype-dependent miRNA signatures in sporadic Creutzfeldt-Jakob disease are accompanied by alterations in miRNA silencing machinery and biogenesis.

PubMed

Llorens, Franc; Thüne, Katrin; Martí, Eulàlia; Kanata, Eirini; Dafou, Dimitra; Díaz-Lucena, Daniela; Vivancos, Ana; Shomroni, Orr; Zafar, Saima; Schmitz, Matthias; Michel, Uwe; Fernández-Borges, Natalia; Andréoletti, Olivier; Del Río, José Antonio; Díez, Juana; Fischer, Andre; Bonn, Stefan; Sklaviadis, Theodoros; Torres, Juan Maria; Ferrer, Isidre; Zerr, Inga

2018-01-01

Increasing evidence indicates that microRNAs (miRNAs) are contributing factors to neurodegeneration. Alterations in miRNA signatures have been reported in several neurodegenerative dementias, but data in prion diseases are restricted to ex vivo and animal models. The present study identified significant miRNA expression pattern alterations in the frontal cortex and cerebellum of sporadic Creutzfeldt-Jakob disease (sCJD) patients. These changes display a highly regional and disease subtype-dependent regulation that correlates with brain pathology. We demonstrate that selected miRNAs are enriched in sCJD isolated Argonaute(Ago)-binding complexes in disease, indicating their incorporation into RNA-induced silencing complexes, and further suggesting their contribution to disease-associated gene expression changes. Alterations in the miRNA-mRNA regulatory machinery and perturbed levels of miRNA biogenesis key components in sCJD brain samples reported here further implicate miRNAs in sCJD gene expression (de)regulation. We also show that a subset of sCJD-altered miRNAs are commonly changed in Alzheimer's disease, dementia with Lewy bodies and fatal familial insomnia, suggesting potential common mechanisms underlying these neurodegenerative processes. Additionally, we report no correlation between brain and cerebrospinal fluid (CSF) miRNA-profiles in sCJD, indicating that CSF-miRNA profiles do not faithfully mirror miRNA alterations detected in brain tissue of human prion diseases. Finally, utilizing a sCJD MM1 mouse model, we analyzed the miRNA deregulation patterns observed in sCJD in a temporal manner. While fourteen sCJD-related miRNAs were validated at clinical stages, only two of those were changed at early symptomatic phase, suggesting that the miRNAs altered in sCJD may contribute to later pathogenic processes. Altogether, the present work identifies alterations in the miRNA network, biogenesis and miRNA-mRNA silencing machinery in sCJD, whereby contributions to disease mechanisms deserve further investigation.

Maillard reaction versus other nonenzymatic modifications in neurodegenerative processes.

PubMed

Pamplona, Reinald; Ilieva, Ekaterina; Ayala, Victoria; Bellmunt, Maria Josep; Cacabelos, Daniel; Dalfo, Esther; Ferrer, Isidre; Portero-Otin, Manuel

2008-04-01

Nonenzymatic protein modifications are generated from direct oxidation of amino acid side chains and from reaction of the nucleophilic side chains of specific amino acids with reactive carbonyl species. These reactions give rise to specific markers that have been analyzed in different neurodegenerative diseases sharing protein aggregation, such as Alzheimer's disease, Pick's disease, Parkinson's disease, dementia with Lewy bodies, Creutzfeldt-Jakob disease, and amyotrophic lateral sclerosis. Collectively, available data demonstrate that oxidative stress homeostasis, mitochondrial function, and energy metabolism are key factors in determining the disease-specific pattern of protein molecular damage. In addition, these findings suggest the lack of a "gold marker of oxidative stress," and, consequently, they strengthen the need for a molecular dissection of the nonenzymatic reactions underlying neurodegenerative processes.

Copper and the Prion Protein: Methods, Structures, Function, and Disease

NASA Astrophysics Data System (ADS)

Millhauser, Glenn L.

2007-05-01

The transmissible spongiform encephalopathies (TSEs) arise from conversion of the membrane-bound prion protein from PrPC to PrPSc. Examples of the TSEs include mad cow disease, chronic wasting disease in deer and elk, scrapie in goats and sheep, and kuru and Creutzfeldt-Jakob disease in humans. Although the precise function of PrPC in healthy tissues is not known, recent research demonstrates that it binds Cu(II) in an unusual and highly conserved region of the protein termed the octarepeat domain. This review describes recent connections between copper and PrPC, with an emphasis on the electron paramagnetic resonance elucidation of the specific copper-binding sites, insights into PrPC function, and emerging connections between copper and prion disease.

Neuronal antibodies in patients with suspected or confirmed sporadic Creutzfeldt-Jakob disease

PubMed Central

Rossi, Meghan; Mead, Simon; Collinge, John; Rudge, Peter; Vincent, Angela

2015-01-01

Objectives There have been reports of patients with antibodies to neuronal antigens misdiagnosed as sporadic Creutzfeldt-Jakob disease (sCJD). Conversely, low levels of antibodies to neuronal proteins have been reported in patients with sCJD. However, the frequency of misdiagnoses, or of antibodies in patients with subsequently confirmed sCJD, is not clear. Methods We reviewed 256 consecutive cases of sCJD seen in the National Prion Clinic, of whom 150 had sera previously referred for selected antibody tests. Eighty-two available samples were retested for antibodies to N-methyl-d-aspartate receptor (NMDAR), the glycine receptor (GlyR), voltage-gated potassium channel (VGKC)-complex and the associated proteins, leucine-rich glioma inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2). Results Four of the initial 150 sera referred were positive; two had antibodies to NMDAR, and two to the VGKC-complex, one of which was also positive for GlyR antibodies. Of the 82 sCJD sera retested, one had VGKC-complex antibodies confirming the previous result, two had CASPR2 and GlyR antibodies and one had CASPR2 and NMDAR antibodies; all antibodies were at low levels. Over the same period three patients with autoimmune encephalitis and high VGKC-complex antibodies were initially referred as sCJD. Conclusions This study indicates that <5% patients with sCJD develop serum antibodies to these neuronal antigens and, when positive, only at low titres. By contrast, three patients referred with possible prion disease had a clinical picture in keeping with autoimmune encephalitis and very high VGKC-complex/LGI1 antibodies. Low titres of neuronal antibodies occur only rarely in suspected patients with sCJD and when present should be interpreted with caution. PMID:25246643

Batch recall of French plasma-derived products due to variant Creutzfeldt-Jakob disease risk: the psychological impact on haemophilic patients, changes in their therapeutic demands and behaviour and ethical considerations.

PubMed

Aouba, A; Harroche, A; Frenzel, L; Torchet, M-F; Rothschild, C; François, I; Mamzer-Bruneel, M-F

2015-01-01

The choice of plasma-derived products (PdP) vs. recombinant products (RP) for treating haemophilia is influenced by the infectious and perceived safety of the products. Batch recall of PdP due to the risk of variant Creutzfeldt-Jakob disease (vCJD) may have unfavourable psychological impacts on haemophilia patients and influence their product preferences. This study aimed to assess the psychological impact of batch recalls of PdP in six haemophilia patients and their therapeutic demands, and to discuss the ethical problems in physicians' management of this event. A survey was conducted using a new interview form and an existing anxiety and depression questionnaire. Batch recalls produce recurrent negative emotional outcomes in haemophiliacs and their families. The quality, understanding and efficiency of the batch recall announcements were unsatisfactory in some respects. Only one patient still had some of the vials in question, and only three patients understood the real reason for the batch recall. Four patients asked to change their PdP for RP; a fifth patient was considering doing so. Here, topics for discussion include the delivery of an unclear message to patients about a very uncertain risk of a frightening disease, the reasons to maintain PdP when RP are largely available, except in specific cases, and the related discomfort for caregivers. The ethical questions revealed by batch recalls and the high psychological impact of vCJD risk on patients can no longer be ignored, and require surveys assessing the rationales and choices of the healthcare authorities, manufacturers, prescribers and users. © 2014 John Wiley & Sons Ltd.

Voltage-Gated Potassium Channel Autoimmunity Mimicking Creutzfeldt-Jakob Disease

PubMed Central

Geschwind, Michael D.; Tan, K. Meng; Lennon, Vanda A.; Barajas, Ramon F.; Haman, Aissa; Klein, Christopher J.; Josephson, S. Andrew; Pittock, Sean J.

2009-01-01

Background Rapidly progressive dementia has a variety of causes, including Creutzfeldt-Jakob disease (CJD) and neuronal voltage-gated potassium channel (VGKC) autoantibody–associated encephalopathy. Objective To describe patients thought initially to have CJD but found subsequently to have immunotherapy-responsive VGKC autoimmunity. Design Observational, prospective case series. Setting Department of Neurology, Mayo Clinic, and the Memory and Aging Center, University of California, San Francisco. Patients A clinical serologic cohort of 15 patients referred for paraneoplastic autoantibody evaluation. Seven patients were evaluated clinically by at least one of us. Clinical information for the remaining patients was obtained by physician interview or medical record review. Main Outcome Measures Clinical features, magnetic resonance imaging abnormalities, electroencephalographic patterns, cerebrospinal fluid analyses, and responses to immunomodulatory therapy. Results All the patients presented subacutely with neurologic manifestations, including rapidly progressive dementia, myoclonus, extrapyramidal dysfunction, visual hallucinations, psychiatric disturbance, and seizures; most (60%) satisfied World Health Organization diagnostic criteria for CJD. Magnetic resonance imaging abnormalities included cerebral cortical diffusion-weighted imaging hyperintensities. Electroencephalographic abnormalities included diffuse slowing, frontal intermittent rhythmic delta activity, and focal epileptogenic activity but not periodic sharp wave complexes. Cerebrospinal fluid 14-3-3 protein or neuron-specific enolase levels were elevated in 5 of 8 patients. Hyponatremia was common (60%). Neoplasia was confirmed histologically in 5 patients (33%) and was suspected in another 5. Most patients’ conditions (92%) improved after immunomodulatory therapy. Conclusions Clinical, radiologic, electrophysiologic, and laboratory findings in VGKC autoantibody–associated encephalopathy may be confused with those of CJD. Serologic evaluation for markers of neurologic autoimmunity, including VGKC autoantibodies, may be warranted in suspected CJD cases. PMID:18852349

Rapid and Highly Sensitive Detection of Variant Creutzfeldt - Jakob Disease Abnormal Prion Protein on Steel Surfaces by Protein Misfolding Cyclic Amplification: Application to Prion Decontamination Studies

PubMed Central

Belondrade, Maxime; Nicot, Simon; Béringue, Vincent; Coste, Joliette; Lehmann, Sylvain; Bougard, Daisy

2016-01-01

The prevalence of variant Creutzfeldt-Jakob disease (vCJD) in the population remains uncertain, although it has been estimated that 1 in 2000 people in the United Kingdom are positive for abnormal prion protein (PrPTSE) by a recent survey of archived appendix tissues. The prominent lymphotropism of vCJD prions raises the possibility that some surgical procedures may be at risk of iatrogenic vCJD transmission in healthcare facilities. It is therefore vital that decontamination procedures applied to medical devices before their reprocessing are thoroughly validated. A current limitation is the lack of a rapid model permissive to human prions. Here, we developed a prion detection assay based on protein misfolding cyclic amplification (PMCA) technology combined with stainless-steel wire surfaces as carriers of prions (Surf-PMCA). This assay allowed the specific detection of minute quantities (10−8 brain dilution) of either human vCJD or ovine scrapie PrPTSE adsorbed onto a single steel wire, within a two week timeframe. Using Surf-PMCA we evaluated the performance of several reference and commercially available prion-specific decontamination procedures. Surprisingly, we found the efficiency of several marketed reagents to remove human vCJD PrPTSE was lower than expected. Overall, our results demonstrate that Surf-PMCA can be used as a rapid and ultrasensitive assay for the detection of human vCJD PrPTSE adsorbed onto a metallic surface, therefore facilitating the development and validation of decontamination procedures against human prions. PMID:26800081

Dura mater graft-associated Creutzfeldt-Jakob disease with 30-year incubation period.

PubMed

Shijo, Masahiro; Honda, Hiroyuki; Koyama, Sachiko; Ishitsuka, Koji; Maeda, Koichiro; Kuroda, Junya; Tanii, Mitsugu; Kitazono, Takanari; Iwaki, Toru

2017-06-01

Over 60% of all patients with dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) have been diagnosed in Japan. The incubation period has ranged from 1 to 30 years and the age at onset from 15 to 80 years. Here, we report a 77-year-old male Japanese autopsied dCJD case with the longest incubation period so far in Japan. He received a cadaveric dural graft at the right cranial convexity following a craniotomy for meningioma at the age of 46. At 30 years post-dural graft placement, disorientation was observed as an initial symptom of dCJD. He rapidly began to present with inconsistent speech, cognitive impairment and tremor of the left upper extremity. Occasional myoclonic jerks were predominantly observed on the left side. Brain MRI presented hyperintense signals on diffusion-weighted and T2-weighted images, at the right cerebral cortex. The most hyperintense lesion was located at the right parietal lobe, where the dura mater graft had been transplanted. Single-photon emission CT scan showed markedly decreased cerebral blood flow at the right parietal lobe. EEG revealed diffuse and slow activities with periodic sharp-wave complex discharges seen in the right parietal, temporal and occipital lobes. He died of pneumonia 9 months after onset. Brain pathology revealed non-plaque-type dCJD. Laterality of neuropathological changes, including spongiform change, neuronal loss, gliosis or PrP deposits, was not evident. Western blot analysis showed type 1 PrP CJD . Alzheimer-type pathology and PSP-like pathology were also observed. © 2016 Japanese Society of Neuropathology.

A Low-Molecular-Weight Ferroxidase Is Increased in the CSF of sCJD Cases: CSF Ferroxidase and Transferrin as Diagnostic Biomarkers for sCJD

PubMed Central

Haldar, Swati; Beveridge, ’Alim J.; Wong, Joseph; Singh, Ajay; Galimberti, Daniela; Borroni, Barbara; Zhu, Xiongwei; Blevins, Janis; Greenlee, Justin; Perry, George; Mukhopadhyay, Chinmay K.; Schmotzer, Christine

2013-01-01

Abstract Aims: Most biomarkers used for the premortem diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) are surrogate in nature, and provide suboptimal sensitivity and specificity. Results: We report that CJD-associated brain iron dyshomeostasis is reflected in the cerebrospinal fluid (CSF), providing disease-specific diagnostic biomarkers. Analysis of 290 premortem CSF samples from confirmed cases of CJD, Alzheimer's disease, and other dementias (DMs), and 52 non-DM (ND) controls revealed a significant difference in ferroxidase (Frx) activity and transferrin (Tf) levels in sporadic Creutzfeldt-Jakob disease (sCJD) relative to other DM and ND controls. A combination of CSF Frx and Tf discriminated sCJD from other DMs with a sensitivity of 86.8%, specificity of 92.5%, accuracy of 88.9%, and area-under-the receiver-operating-characteristic (ROC) curve of 0.94. This combination provided a similar diagnostic accuracy in discriminating CJD from rapidly progressing cases who died within 6 months of sample collection. Surprisingly, ceruloplasmin and amyloid precursor protein, the major brain Frxs, displayed minimal activity in the CSF. Most of the Frx activity was concentrated in the <3-kDa fraction in normal and diseased CSF, and resisted heat and proteinase-K treatment. Innovation: (i) A combination of CSF Frx and Tf provides disease-specific premortem diagnostic biomarkers for sCJD. (ii) A novel, nonenzymatic, nonprotein Frx predominates in human CSF that is distinct from the currently known CSF Frxs. Conclusion: The underlying cause of iron imbalance is distinct in sCJD relative to other DMs associated with the brain iron imbalance. Thus, change in the CSF levels of iron-management proteins can provide disease-specific biomarkers and insight into the cause of iron imbalance in neurodegenerative conditions. Antioxid. Redox Signal. 19, 1662–1675. PMID:23379482

Mad cow disease--the OR connection.

PubMed

Hansel, P A

1999-08-01

Creutzfeldt-Jakob disease (CJD) is one of the transmissible spongiform encephalopathies, a group of fatal, neurodegenerative disorders affecting both humans and animals. The causative agent is the prion, which is still being researched and is controversial. In the 1980s, bovine spongiform encephalopathy brought much media attention to these diseases. Bovine spongiform encephalopathy is the result of faulty industrial practices that produced cattle feed contaminated by prions. In the 1990s, a new variant of CJD (i.e., nvCJD) appeared in Britain. Researchers believe that nvCJD was passed to humans through oral consumption of contaminated beef. This article describes the history, causative agent, mode of transmission, clinical features and course, diagnosis, treatment, and decontamination and sterilization guidelines for this baffling disease.

Prion protein immunocytochemistry helps to establish the true incidence of prion diseases.

PubMed

Lantos, P L; McGill, I S; Janota, I; Doey, L J; Collinge, J; Bruce, M T; Whatley, S A; Anderton, B H; Clinton, J; Roberts, G W

1992-11-23

Creutzfeldt-Jakob disease (CJD) and Gerstmann-Strüssler-Scheinker disease (GSSD) are transmissible spongiform encephalopathies or prion diseases affecting man. It has been reported that prion diseases may occur without the histological hallmarks of spongiform encephalopathies: vacuolation of the cerebral grey matter, neuronal loss and astrocytosis. These cases without characteristic neuropathology may go undiagnosed and consequently the true incidence of transmissible dementias is likely to have been under-estimated. Immunocytochemistry using antibodies to prion protein gives positive staining of these cases, albeit the pattern of immunostaining differs from that seen in typical forms. Accumulation of prion protein is a molecular hallmark of prion diseases, and thus a reproducible, speedy and cost-efficient immunocytochemical screening of unusual dementias may help to establish the true incidence of prion diseases.

Policy understanding of science, public trust and the BSE-CJD crisis.

PubMed

Jacob, M; Hellström, T

2000-11-03

The article investigates how institutional factors can produce risk using the Bovine Spongiform Encephalopathy (BSE)-Creutzfeldt-Jakob Disease (CJD) crisis in Britain as a case example. The paper focuses on the way policymakers understand science, and the role of precaution in issues of high uncertainty. It is argued that the failure to fully appreciate the complexity of the BSE-CJD situation resided in institutional arrangements that predisposed decision makers to adopt a counter productive approach in handling situations of high scientific uncertainty on the policy level. The article will demonstrate how these factors played out in the BSE-CJD crisis.

Case Studies Illustrating Focal Alzheimer's, Fluent Aphasia, Late-Onset Memory Loss, and Rapid Dementia.

PubMed

Camsari, Gamze Balci; Murray, Melissa E; Graff-Radford, Neill R

2016-08-01

Many dementia subtypes have more shared signs and symptoms than defining ones. We review 8 cases with 4 overlapping syndromes and demonstrate how to distinguish the cases. These include focal cortical presentations of Alzheimer's disease (AD; posterior cortical atrophy and corticobasal syndrome [CBS]), fluent aphasia (semantic dementia and logopenic aphasia), late-onset slowly progressive dementia (hippocampal sclerosis and limbic predominant AD) and rapidly progressive dementia (Creutzfeldt-Jakob disease and limbic encephalitis). Recognizing the different syndromes can help the clinician to improve their diagnostic skills, leading to improved patient outcomes by early and accurate diagnosis, prompt treatment, and appropriate counseling and guidance. Copyright © 2016 Elsevier Inc. All rights reserved.

[A case of MM1+2 Creutzfeldt-Jakob disease with a longitudinal study of EEG and MRI].

PubMed

Katsube, Mizuho; Shiota, Yuri; Harada, Takayuki; Shibata, Hiroshi; Nagai, Atsushi

2013-11-01

We report a case of definite MM1 + 2 sporadic Creutzfeldt-Jakob disease (sCJD). A 66-year-old woman was admitted to our hospital with memory disturbance and disorientation for three months. On admission she presented a progressive cognitive insufficiency. Electroencephalography (EEG) revealed a frontal intermittent rhythmical delta activity (FIRDA) and the brain magnetic resonance imaging (MRI) showed high signal intensities in cerebral cortex on diffusion weighted images (DWI). After four months from the onset, she reached the akinetic mutism state followed by myoclonus. Follow up examination revealed that periodic synchronous discharge (PSD) was found in EEG, and DWI revealed enlargement of high signal intensity lesions in cerebral cortex. At seven months from the onset, PSD and high signal intensities of cortex became unclear with disappearance of myoclonus, and brain white matter lesions were evident on MRI. Serial studies of EEG and MRI revealed that PSD generalized from frontal lobe dominant pattern, while high signal intensity lesions of cortex diffusely increased on DWI. At ten months from the onset patient died. Pathological examination in brain showed moderate and diffuse neuronal cell loss and gliosis in cerebral cortex corresponding with DWI changes. The genotype at codon 129 of the prion protein (PrP) was homozygous methionine (MM) and the type of protease-resistant PrP (PrPres) was the mixed type of 1 and 2 in Western blot analysis. It has been rare to analyze the changes of EEG and MRI in the entire stage and to investigate pathological finding in the case of sCJD-MM1 + 2. A longitudinal examination of EEG and MRI is useful for early diagnosis of CJD. Also we could correlate these findings with clinical and histopathological phenotype.

Geographic exposure risk of variant Creutzfeldt-Jakob disease in US blood donors: a risk-ranking model to evaluate alternative donor-deferral policies.

PubMed

Yang, Hong; Huang, Yin; Gregori, Luisa; Asher, David M; Bui, Travis; Forshee, Richard A; Anderson, Steven A

2017-04-01

Variant Creutzfeldt-Jakob disease (vCJD) has been transmitted by blood transfusion (TTvCJD). The US Food and Drug Administration (FDA) recommends deferring blood donors who resided in or traveled to 30 European countries where they may have been exposed to bovine spongiform encephalopathy (BSE) through beef consumption. Those recommendations warrant re-evaluation, because new cases of BSE and vCJD have markedly abated. The FDA developed a risk-ranking model to calculate the geographic vCJD risk using country-specific case rates and person-years of exposure of US blood donors. We used the reported country vCJD case rates, when available, or imputed vCJD case rates from reported BSE and UK beef exports during the risk period. We estimated the risk reduction and donor loss should the deferral be restricted to a few high-risk countries. We also estimated additional risk reduction by leukocyte reduction (LR) of red blood cells (RBCs). The United Kingdom, Ireland, and France had the greatest vCJD risk, contributing approximately 95% of the total risk. The model estimated that deferring US donors who spent extended periods of time in these three countries, combined with currently voluntary LR (95% of RBC units), would reduce the vCJD risk by 89.3%, a reduction similar to that achieved under the current policy (89.8%). Limiting deferrals to exposure in these three countries would potentially allow donations from an additional 100,000 donors who are currently deferred. Our analysis suggests that a deferral option focusing on the three highest risk countries would achieve a level of blood safety similar to that achieved by the current policy. © 2016 AABB.

EEG Differences in Two Clinically Similar Rapid Dementias: Voltage-Gated Potassium Channel Complex-Associated Autoimmune Encephalitis and Creutzfeldt-Jakob Disease.

PubMed

Freund, Brin; Probasco, John C; Cervenka, Mackenzie C; Sutter, Raoul; Kaplan, Peter W

2018-05-01

Distinguishing treatable causes for rapidly progressive dementia from those that are incurable is vital. Creutzfeldt-Jakob disease (CJD) and voltage-gated potassium channel complex-associated autoimmune encephalitis (VGKC AE) are 2 such conditions with disparate outcomes and response to treatment. To determine the differences in electroencephalography between CJD and VGKC AE, we performed a retrospective review of medical records and examined clinical data, neuroimaging, and electroencephalographs performed in patients admitted for evaluation for rapidly progressive dementia diagnosed with CJD and VGKC AE at the Johns Hopkins Hospital and Bayview Medical Center between January 1, 2007 and December 31, 2015. More patients in the VGKC AE group had seizures (12/17) than those with CJD (3/14; P = .008). Serum sodium levels were lower in those with VGKC AE ( P = .001). Cerebrospinal fluid (CSF) white blood cell count was higher in VGKC AE ( P = .008). CSF protein 14-3-3 ( P = .018) was more commonly detected in CJD, and tau levels were higher in those with CJD ( P < .006). On neuroimaging, diffusion restriction in the cortex ( P = .001), caudate ( P < .001), and putamen ( P = .001) was more frequent in CJD. Periodic sharp wave complexes ( P = .001) and generalized suppressed activity ( P = .008) were more common on initial EEG in CJD. On serial EEGs, generalized periodic discharges ( P = .004), generalized suppressed activity (P=0.008), and periodic sharp wave complexes ( P < .001) were detected more in CJD. This study shows that there are a number of differentiating features between CJD and VGKC AE, and electroencephalography can aid in their diagnoses. Performing serial EEGs better delineates these conditions.

The reporting of theoretical health risks by the media: Canadian newspaper reporting of potential blood transmission of Creutzfeldt-Jakob disease

PubMed Central

Wilson, Kumanan; Code, Catherine; Dornan, Christopher; Ahmad, Nadya; Hébert, Paul; Graham, Ian

2004-01-01

Background The media play an important role at the interface of science and policy by communicating scientific information to the public and policy makers. In issues of theoretical risk, in which there is scientific uncertainty, the media's role as disseminators of information is particularly important due to the potential to influence public perception of the severity of the risk. In this article we describe how the Canadian print media reported the theoretical risk of blood transmission of Creutzfeldt-Jakob disease (CJD). Methods We searched 3 newspaper databases for articles published by 6 major Canadian daily newspapers between January 1990 and December 1999. We identified all articles relating to blood transmission of CJD. In duplicate we extracted information from the articles and entered the information into a qualitative software program. We compared the observations obtained from this content analysis with information obtained from a previous policy analysis examining the Canadian blood system's decision-making concerning the potential transfusion transmission of CJD. Results Our search identified 245 relevant articles. We observed that newspapers in one instance accelerated a policy decision, which had important resource and health implication, by communicating information on risk to the public. We also observed that newspapers primarily relied upon expert opinion (47 articles) as opposed to published medical evidence (28 articles) when communicating risk information. Journalists we interviewed described the challenges of balancing their responsibility to raise awareness of potential health threats with not unnecessarily arousing fear amongst the public. Conclusions Based on our findings we recommend that journalists report information from both expert opinion sources and from published studies when communicating information on risk. We also recommend researchers work more closely with journalists to assist them in identifying and appraising relevant scientific information on risk. PMID:14706119

[A review of the current research on prions. The evidence suggests the possibility of transmission of the mad cow disease to humans].

PubMed

Grandien, M; Wahren, B

1998-11-25

Further evidence of the transmissibility of bovine spongiform encephalopathy (BSE) across the species barrier from cow to man has been derived from epidemiological analysis and the characterisation of prion strains. Recent research has shown the persistence of prions after experimental transmission to resistant murine species, and subclinical persistence in cows. The accumulation of pathological prion proteins in tonsils and appendix has been demonstrated prior to clinical confirmation of the presence of the new variant of Creutzfeldt-Jakob disease. Current prion research is focused on the involvement of B lymphocytes as carriers, on the species barrier and cellular receptors, and on macromolecules involved in the conformational change from normal to pathological prion proteins.

[Anesthetic management of a patient with Creutzfeldt-Jacob disease undergoing tracheal separation].

PubMed

Kanzaki, Rieko; Hamada, Hiroshi; Fukuda, Hideki; Kawamoto, Masashi

2012-10-01

We gave anesthesia for tracheal separation in a patient with Creutzfeldt-Jakob disease. The patient, a 33-year-old woman, was bedridden and unable to communicate, and was going to undergo a tracheal separation procedure for repeated bouts of aspiration pneumonia. After a tracheostomy with local anesthesia and sedation with propofol, general anesthesia was induced and maintained with propofol (1.5-3.0 microg x ml(-1), target controlled infusion) and remifentanil (0.05-0.15 microg x kg(-1) x min(-1)). We did not use an anesthetic apparatus from the standpoint of infection control, and provided manual ventilation with a disposable Jackson-Rees circuit. During the operation, an entropy monitor indicated alternating extremely low (0-10) and high (90-100) values without circulatory change, probably due to a previously existing electroencephalographic abnormality. The surgery was uneventful, and spontaneous breathing and eyelid opening occurred about 10 minutes after discontinuation of remifentanil and propofol. In such infected patients, abnormal prion proteins can exist outside of the central nervous system throughout the period of anesthetic management. Therefore, careful infection control must be undertaken, even if the surgical site is not directly related to the central nervous system.

Disease Burden of 32 Infectious Diseases in the Netherlands, 2007-2011.

PubMed

van Lier, Alies; McDonald, Scott A; Bouwknegt, Martijn; Kretzschmar, Mirjam E; Havelaar, Arie H; Mangen, Marie-Josée J; Wallinga, Jacco; de Melker, Hester E

2016-01-01

Infectious disease burden estimates provided by a composite health measure give a balanced view of the true impact of a disease on a population, allowing the relative impact of diseases that differ in severity and mortality to be monitored over time. This article presents the first national disease burden estimates for a comprehensive set of 32 infectious diseases in the Netherlands. The average annual disease burden was computed for the period 2007-2011 for selected infectious diseases in the Netherlands using the disability-adjusted life years (DALY) measure. The pathogen- and incidence-based approach was adopted to quantify the burden due to both morbidity and premature mortality associated with all short and long-term consequences of infection. Natural history models, disease progression probabilities, disability weights, and other parameters were adapted from previous research. Annual incidence was obtained from statutory notification and other surveillance systems, which was corrected for under-ascertainment and under-reporting. The highest average annual disease burden was estimated for invasive pneumococcal disease (9444 DALYs/year; 95% uncertainty interval [UI]: 8911-9961) and influenza (8670 DALYs/year; 95% UI: 8468-8874), which represents 16% and 15% of the total burden of all 32 diseases, respectively. The remaining 30 diseases ranked by number of DALYs/year from high to low were: HIV infection, legionellosis, toxoplasmosis, chlamydia, campylobacteriosis, pertussis, tuberculosis, hepatitis C infection, Q fever, norovirus infection, salmonellosis, gonorrhoea, invasive meningococcal disease, hepatitis B infection, invasive Haemophilus influenzae infection, shigellosis, listeriosis, giardiasis, hepatitis A infection, infection with STEC O157, measles, cryptosporidiosis, syphilis, rabies, variant Creutzfeldt-Jakob disease, tetanus, mumps, rubella, diphtheria, and poliomyelitis. The very low burden for the latter five diseases can be attributed to the National Immunisation Programme. The average disease burden per individual varied from 0.2 (95% UI: 0.1-0.4) DALYs per 100 infections for giardiasis, to 5081 and 3581 (95% UI: 3540-3611) DALYs per 100 infections for rabies and variant Creutzfeldt-Jakob disease, respectively. For guiding and supporting public health policy decisions regarding the prioritisation of interventions and preventive measures, estimates of disease burden and the comparison of burden between diseases can be informative. Although the collection of disease-specific parameters and estimation of incidence is a process subject to continuous improvement, the current study established a baseline for assessing the impact of future public health initiatives.

Risk of transmission of bovine spongiform encephalopathy to humans in the United States: report of the Council on Scientific Affairs. American Medical Association.

PubMed

Tan, L; Williams, M A; Khan, M K; Champion, H C; Nielsen, N H

The risk of possible transmission of bovine spongiform encephalopathy (BSE) in the United States is a substantial public health concern. To systematically review the current scientific literature and discuss legislation and regulations that have been implemented to prevent the disease. Literature review using the MEDLINE, EMBASE, and Lexis/Nexis databases for 1975 through 1997 on the terms bovine spongiform encephalopathy, prion diseases, prions, and Creutzfeldt-Jakob syndrome. The Internet was used to identify regulatory actions and health surveillance. MEDLINE, EMBASE, and Lexis/Nexis databases were searched from 1975 through 1997 for English-language articles that provided information on assessment of transmission risk. Unique circumstances in the United Kingdom caused the emergence and propagation of BSE in cattle, including widespread use of meat and bonemeal cattle feed derived from scrapie-infected sheep and the adoption of a new type of processing that did not reduce the amount of infectious prions prior to feeding. Many of these circumstances do not exist in the United States. In the United Kingdom, new variant Creutzfeldt-Jakob disease probably resulted from the ingestion of BSE-contaminated processed beef. The United Kingdom and the European Union now have strong regulations in place to stop the spread of BSE. While BSE has not been observed in the United States, the US government has surveillance and response plans in effect. Current risk of transmission of BSE in the United States is minimal because (1) BSE has not been shown to exist in this country; (2) adequate regulations exist to prevent entry of foreign sources of BSE into the United States; (3) adequate regulations exist to prevent undetected cases of BSE from uncontrolled amplification within the US cattle population; and (4) adequate preventive guidelines exist to prevent high-risk bovine materials from contaminating products intended for human consumption.

Neuronal antibodies in patients with suspected or confirmed sporadic Creutzfeldt-Jakob disease.

PubMed

Rossi, Meghan; Mead, Simon; Collinge, John; Rudge, Peter; Vincent, Angela

2015-06-01

There have been reports of patients with antibodies to neuronal antigens misdiagnosed as sporadic Creutzfeldt-Jakob disease (sCJD). Conversely, low levels of antibodies to neuronal proteins have been reported in patients with sCJD. However, the frequency of misdiagnoses, or of antibodies in patients with subsequently confirmed sCJD, is not clear. We reviewed 256 consecutive cases of sCJD seen in the National Prion Clinic, of whom 150 had sera previously referred for selected antibody tests. Eighty-two available samples were retested for antibodies to N-methyl-d-aspartate receptor (NMDAR), the glycine receptor (GlyR), voltage-gated potassium channel (VGKC)-complex and the associated proteins, leucine-rich glioma inactivated 1 (LGI1) and contactin-associated protein 2 (CASPR2). Four of the initial 150 sera referred were positive; two had antibodies to NMDAR, and two to the VGKC-complex, one of which was also positive for GlyR antibodies. Of the 82 sCJD sera retested, one had VGKC-complex antibodies confirming the previous result, two had CASPR2 and GlyR antibodies and one had CASPR2 and NMDAR antibodies; all antibodies were at low levels. Over the same period three patients with autoimmune encephalitis and high VGKC-complex antibodies were initially referred as sCJD. This study indicates that <5% patients with sCJD develop serum antibodies to these neuronal antigens and, when positive, only at low titres. By contrast, three patients referred with possible prion disease had a clinical picture in keeping with autoimmune encephalitis and very high VGKC-complex/LGI1 antibodies. Low titres of neuronal antibodies occur only rarely in suspected patients with sCJD and when present should be interpreted with caution. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Absence of Evidence for a Causal Link between Bovine Spongiform Encephalopathy Strain Variant L-BSE and Known Forms of Sporadic Creutzfeldt-Jakob Disease in Human PrP Transgenic Mice.

PubMed

Jaumain, Emilie; Quadrio, Isabelle; Herzog, Laetitia; Reine, Fabienne; Rezaei, Human; Andréoletti, Olivier; Laude, Hubert; Perret-Liaudet, Armand; Haïk, Stéphane; Béringue, Vincent

2016-12-01

Prions are proteinaceous pathogens responsible for subacute spongiform encephalopathies in animals and humans. The prions responsible for bovine spongiform encephalopathy (BSE) are zoonotic agents, causing variant Creutzfeldt-Jakob disease (CJD) in humans. The transfer of prions between species is limited by a species barrier, which is thought to reflect structural incompatibilities between the host cellular prion protein (PrP C ) and the infecting pathological PrP assemblies (PrP Sc ) constituting the prion. A BSE strain variant, designated L-BSE and responsible for atypical, supposedly spontaneous forms of prion diseases in aged cattle, demonstrates zoonotic potential, as evidenced by its capacity to propagate more easily than classical BSE in transgenic mice expressing human PrP C and in nonhuman primates. In humanized mice, L-BSE propagates without any apparent species barrier and shares similar biochemical PrP Sc signatures with the CJD subtype designated MM2-cortical, thus opening the possibility that certain CJD cases classified as sporadic may actually originate from L-type BSE cross-transmission. To address this issue, we compared the biological properties of L-BSE and those of a panel of CJD subtypes representative of the human prion strain diversity using standard strain-typing criteria in human PrP transgenic mice. We found no evidence that L-BSE causes a known form of sporadic CJD. Since the quasi-extinction of classical BSE, atypical BSE forms are the sole BSE variants circulating in cattle worldwide. They are observed in rare cases of old cattle, making them difficult to detect. Extrapolation of our results suggests that L-BSE may propagate in humans as an unrecognized form of CJD, and we urge both the continued utilization of precautionary measures to eliminate these agents from the human food chain and active surveillance for CJD phenotypes in the general population. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Prion 2005: Between Fundamentals and Society's Needs.

PubMed

Treiber, Carina

2006-01-25

Prion diseases for the most part affect individuals older than 60 years of age and share features with other diseases characterized by protein deposits in the brain, such as Alzheimer's disease and Parkinson's disease. The international conference "Prion 2005: Between Fundamentals and Society's Needs," organized by the German Transmissible Spongiform Encephalopathies Research Platform, aimed to integrate and coordinate the research efforts of participants to better achieve prevention, treatment, control, and management of prion diseases, including Creutzfeldt-Jakob disease and fatal familial insomnia in humans. Several main topics were discussed, such as the molecular characteristics of prion strains, the cell biology of cellular and pathogenic forms of the prion proteins, the pathogenesis of the diseases they cause, emerging problems, and promising approaches for therapy and new diagnostic tools. The presentations at the Prion 2005 conference provided new insights in both basic and applied research, which will have broad implications for society's needs.

Presence of voltage-gated potassium channel complex antibody in a case of genetic prion disease

PubMed Central

Jammoul, Adham; Lederman, Richard J; Tavee, Jinny; Li, Yuebing

2014-01-01

Voltage-gated potassium channel (VGKC) complex antibody-mediated encephalitis is a recently recognised entity which has been reported to mimic the clinical presentation of Creutzfeldt-Jakob disease (CJD). Testing for the presence of this neuronal surface autoantibody in patients presenting with subacute encephalopathy is therefore crucial as it may both revoke the bleak diagnosis of prion disease and allow institution of potentially life-saving immunotherapy. Tempering this optimistic view is the rare instance when a positive VGKC complex antibody titre occurs in a definite case of prion disease. We present a pathologically and genetically confirmed case of CJD with elevated serum VGKC complex antibody titres. This case highlights the importance of interpreting the result of a positive VGKC complex antibody with caution and in the context of the overall clinical manifestation. PMID:24903967

Presence of voltage-gated potassium channel complex antibody in a case of genetic prion disease.

PubMed

Jammoul, Adham; Lederman, Richard J; Tavee, Jinny; Li, Yuebing

2014-06-05

Voltage-gated potassium channel (VGKC) complex antibody-mediated encephalitis is a recently recognised entity which has been reported to mimic the clinical presentation of Creutzfeldt-Jakob disease (CJD). Testing for the presence of this neuronal surface autoantibody in patients presenting with subacute encephalopathy is therefore crucial as it may both revoke the bleak diagnosis of prion disease and allow institution of potentially life-saving immunotherapy. Tempering this optimistic view is the rare instance when a positive VGKC complex antibody titre occurs in a definite case of prion disease. We present a pathologically and genetically confirmed case of CJD with elevated serum VGKC complex antibody titres. This case highlights the importance of interpreting the result of a positive VGKC complex antibody with caution and in the context of the overall clinical manifestation. 2014 BMJ Publishing Group Ltd.

Reflections on a half-century in the field of transmissible spongiform encephalopathy.

PubMed

Brown, Paul

2009-01-01

The subject of transmissible spongiform encephalopathy may properly be said to have begun with the experimental transmission of scrapie by Cuillé and Chelle in 1936, although Creutzfeldt and Jakob had described the disease that bears their names in 1920-21. Thirty more years passed before the human disease was also shown to be transmissible, in 1966, and the following half century has seen the field move from classical biology to molecular biology and genetics, and from 'slow virus' to host-encoded 'prion' protein. Because nothing is more important to the research scientist than the process of seeing a problem and devising ways of solving it, and because we live and die by our publications, as much care should be given to these vehicles of our work and reputations as to the research itself. Four aspects have been chosen for comment: authorship, abbreviations, data presentation, and references. In addition to the 'science of research' there are several 'para-scientific' activities that may be categorized as 'the politics of research', which include administrative duties, committees (e.g., scientific meetings, grant organizations), journal/book editing, peer reviewing, and public relations Many young scientists are either unaware or dismissive of the importance of these 'scientific distractions', but their potential for influencing the direction of a field of research becomes increasingly evident as careers unfold. They are subject to uses and abuses, and some guidance and examples are given by way of illustration, particular attention being paid to the process of manuscript review which, because of its anonymity, is the most vulnerable to abuse. As public and government interest in prions wanes in parallel with the disappearance of iatrogenic and variant Creutzfeldt-Jakob disease, the flow of money to sustain research is in evident jeopardy. With an uncertain future, it nevertheless seems possible that one of two things may breathe new life into the field: either an unforeseen new outbreak of human disease will occur (as has happened in the past), or a cross-fertilization between prions and the larger family of protein misfolding diseases, especially Alzheimer's disease, will bear fruit. For obvious reasons, we should hope for the botanical alternative.

Prevalence of the prion protein gene E211K variant in U.S. cattle

PubMed Central

Heaton, Michael P; Keele, John W; Harhay, Gregory P; Richt, Jürgen A; Koohmaraie, Mohammad; Wheeler, Tommy L; Shackelford, Steven D; Casas, Eduardo; King, D Andy; Sonstegard, Tad S; Van Tassell, Curtis P; Neibergs, Holly L; Chase, Chad C; Kalbfleisch, Theodore S; Smith, Timothy PL; Clawson, Michael L; Laegreid, William W

2008-01-01

Background In 2006, an atypical U.S. case of bovine spongiform encephalopathy (BSE) was discovered in Alabama and later reported to be polymorphic for glutamate (E) and lysine (K) codons at position 211 in the bovine prion protein gene (Prnp) coding sequence. A bovine E211K mutation is important because it is analogous to the most common pathogenic mutation in humans (E200K) which causes hereditary Creutzfeldt – Jakob disease, an autosomal dominant form of prion disease. The present report describes a high-throughput matrix-associated laser desorption/ionization-time-of-flight mass spectrometry assay for scoring the Prnp E211K variant and its use to determine an upper limit for the K211 allele frequency in U.S. cattle. Results The K211 allele was not detected in 6062 cattle, including those from five commercial beef processing plants (3892 carcasses) and 2170 registered cattle from 42 breeds. Multiple nearby polymorphisms in Prnp coding sequence of 1456 diverse purebred cattle (42 breeds) did not interfere with scoring E211 or K211 alleles. Based on these results, the upper bounds for prevalence of the E211K variant was estimated to be extremely low, less than 1 in 2000 cattle (Bayesian analysis based on 95% quantile of the posterior distribution with a uniform prior). Conclusion No groups or breeds of U.S. cattle are presently known to harbor the Prnp K211 allele. Because a carrier was not detected, the number of additional atypical BSE cases with K211 will also be vanishingly low. PMID:18625065

Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders.

PubMed

Islam, Md Torequl

2017-01-01

Reactive species play an important role in physiological functions. Overproduction of reactive species, notably reactive oxygen (ROS) and nitrogen (RNS) species along with the failure of balance by the body's antioxidant enzyme systems results in destruction of cellular structures, lipids, proteins, and genetic materials such as DNA and RNA. Moreover, the effects of reactive species on mitochondria and their metabolic processes eventually cause a rise in ROS/RNS levels, leading to oxidation of mitochondrial proteins, lipids, and DNA. Oxidative stress has been considered to be linked to the etiology of many diseases, including neurodegenerative diseases (NDDs) such as Alzheimer diseases, Amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Multiple sclerosis, and Parkinson's diseases. In addition, oxidative stress causing protein misfold may turn to other NDDs include Creutzfeldt-Jakob disease, Bovine Spongiform Encephalopathy, Kuru, Gerstmann-Straussler-Scheinker syndrome, and Fatal Familial Insomnia. An overview of the oxidative stress and mitochondrial dysfunction-linked NDDs has been summarized in this review.

Transmission of scrapie prions to primate after an extended silent incubation period.

PubMed

Comoy, Emmanuel E; Mikol, Jacqueline; Luccantoni-Freire, Sophie; Correia, Evelyne; Lescoutra-Etchegaray, Nathalie; Durand, Valérie; Dehen, Capucine; Andreoletti, Olivier; Casalone, Cristina; Richt, Juergen A; Greenlee, Justin J; Baron, Thierry; Benestad, Sylvie L; Brown, Paul; Deslys, Jean-Philippe

2015-06-30

Classical bovine spongiform encephalopathy (c-BSE) is the only animal prion disease reputed to be zoonotic, causing variant Creutzfeldt-Jakob disease (vCJD) in humans and having guided protective measures for animal and human health against animal prion diseases. Recently, partial transmissions to humanized mice showed that the zoonotic potential of scrapie might be similar to c-BSE. We here report the direct transmission of a natural classical scrapie isolate to cynomolgus macaque, a highly relevant model for human prion diseases, after a 10-year silent incubation period, with features similar to those reported for human cases of sporadic CJD. Scrapie is thus actually transmissible to primates with incubation periods compatible with their life expectancy, although fourfold longer than BSE. Long-term experimental transmission studies are necessary to better assess the zoonotic potential of other prion diseases with high prevalence, notably Chronic Wasting Disease of deer and elk and atypical/Nor98 scrapie.

Transmission of scrapie prions to primate after an extended silent incubation period

PubMed Central

Comoy, Emmanuel E.; Mikol, Jacqueline; Luccantoni-Freire, Sophie; Correia, Evelyne; Lescoutra-Etchegaray, Nathalie; Durand, Valérie; Dehen, Capucine; Andreoletti, Olivier; Casalone, Cristina; Richt, Juergen A.; Greenlee, Justin J.; Baron, Thierry; Benestad, Sylvie L.; Brown, Paul; Deslys, Jean-Philippe

2015-01-01

Classical bovine spongiform encephalopathy (c-BSE) is the only animal prion disease reputed to be zoonotic, causing variant Creutzfeldt-Jakob disease (vCJD) in humans and having guided protective measures for animal and human health against animal prion diseases. Recently, partial transmissions to humanized mice showed that the zoonotic potential of scrapie might be similar to c-BSE. We here report the direct transmission of a natural classical scrapie isolate to cynomolgus macaque, a highly relevant model for human prion diseases, after a 10-year silent incubation period, with features similar to those reported for human cases of sporadic CJD. Scrapie is thus actually transmissible to primates with incubation periods compatible with their life expectancy, although fourfold longer than BSE. Long-term experimental transmission studies are necessary to better assess the zoonotic potential of other prion diseases with high prevalence, notably Chronic Wasting Disease of deer and elk and atypical/Nor98 scrapie. PMID:26123044

[The truth and present uncertainty about mad cow disease].

PubMed

Suárez Fernández, G

2001-01-01

A historical review is made about Spongiform Encephalopathies which affect both animals and man. This is the base for an epidemiological and predictive analysis of these type of diseases, especially Bovine Spongiform Encephalopathy (BSE) as a present health problem. The scientific certainties or truths, such as the prion theory (PrPc-PrPsc), the low natural infectivity of these group of diseases, the high dose of prions necessary to produce the experimental disease, the species barrier or specificity, the individual susceptibility due to genetic traits, and the low transmission efficiency by the oral route, compared to the parenteral route, agree with the epidemiological observations of human cases of the variant of the Creutzfeldt-Jakob disease (vCJD), which is 0.1 cases per million inhabitants and year. The present and future prediction of BSE should not be alarmist, taking into account the certainties that we know.

Brain-water diffusion coefficients reflect the severity of inherited prion disease

PubMed Central

Hyare, H.; Wroe, S.; Siddique, D.; Webb, T.; Fox, N. C.; Stevens, J.; Collinge, J.; Yousry, T.; Thornton, J. S.

2010-01-01

Objective: Inherited prion diseases are progressive neurodegenerative conditions, characterized by cerebral spongiosis, gliosis, and neuronal loss, caused by mutations within the prion protein (PRNP) gene. We wished to assess the potential of diffusion-weighted MRI as a biomarker of disease severity in inherited prion diseases. Methods: Twenty-five subjects (mean age 45.2 years) with a known PRNP mutation including 19 symptomatic patients, 6 gene-positive asymptomatic subjects, and 7 controls (mean age 54.1 years) underwent conventional and diffusion-weighted MRI. An index of normalized brain volume (NBV) and region of interest (ROI) mean apparent diffusion coefficient (ADC) for the head of caudate, putamen, and pulvinar nuclei were recorded. ADC histograms were computed for whole brain (WB) and gray matter (GM) tissue fractions. Clinical assessment utilized standardized clinical scores. Mann-Whitney U test and regression analyses were performed. Results: Symptomatic patients exhibited an increased WB mean ADC (p = 0.006) and GM mean ADC (p = 0.024) compared to controls. Decreased NBV and increased mean ADC measures significantly correlated with clinical measures of disease severity. Using a stepwise multivariate regression procedure, GM mean ADC was an independent predictor of Clinician's Dementia Rating score (p = 0.001), Barthel Index of activities of daily living (p = 0.001), and Rankin disability score (p = 0.019). Conclusions: Brain volume loss in inherited prion diseases is accompanied by increased cerebral apparent diffusion coefficient (ADC), correlating with increased disease severity. The association between gray matter ADC and clinical neurologic status suggests this measure may prove a useful biomarker of disease activity in inherited prion diseases. GLOSSARY ADAS-Cog = Alzheimer's Disease Assessment Scale–Cognitive subscale; ADC = apparent diffusion coefficient; ADL = Barthel Activities of Daily Living scale; BET = brain extraction tool; BPRS = Brief Psychiatric Rating Scale; BSE = bovine spongiform encephalopathy; CDR = Clinician's Dementia Rating Scale; CGIS = Clinician's Global Impression of Disease; CI = confidence interval; DWI = diffusion-weighted imaging; FLAIR = fluid-attenuated inversion recovery; FOV = field of view; GM = gray matter; LC = left head of caudate; LP = left putamen; LPu = left pulvinar; MMSE = Mini-Mental State Examination; NBV = normalized brain volume; PH = peak height; PL = peak location; RC = right head of caudate; RP = right putamen; RPu = right pulvinar; ROI = region of interest; sCJD = sporadic Creutzfeldt-Jakob disease; TE = echo time; TI = inversion time; TR = repetition time; vCJD = variant Creutzfeldt-Jakob disease; WB = whole brain; WM = white matter. PMID:20177119

A novel copper-hydrogen peroxide formulation for prion decontamination.

PubMed

Solassol, Jerome; Pastore, Manuela; Crozet, Carole; Perrier, Veronique; Lehmann, Sylvain

2006-09-15

With the appearance of variant Creutzfeldt-Jakob disease (CJD) and the detection of infectious prions in the peripheral organs of persons with sporadic CJD, the development of decontamination methods that are compatible with medical equipment has become a major issue. Here, we show that a formulation of copper metal ions in combination with hydrogen peroxide dramatically reduces the level of prion protein (PrP)(Sc) (the scrapie isoform of PrP) present in homogenates of samples from prion-infected brains, including brain samples from humans with CJD. An animal bioassay confirmed the reduction in prion infectivity, indicating that this novel Cu(2+)-H(2)O(2) formulation has great potential for prion decontamination.

Accuracy of a history of blood donation from surrogate witnesses: data from the UK TMER study.

PubMed

Mackenzie, J M; Turner, M; Morris, K; Field, S; Molesworth, A M; Pal, S; Will, R G; Llewelyn, C A; Hewitt, P E

2018-05-15

Look-back studies of blood transfusion in Creutzfeldt-Jakob disease commonly rely on reported history from surrogate witnesses. Data from the UK Transfusion Medicine Epidemiology Review have been analysed to determine the accuracy of the blood donation history provided by the relatives of cases. Our results show that only a small percentage of cases were found to be registered as donors on UK Blood Service (UKBS) databases when there was no family report of blood donation. In contrast, a history of reported donation was less accurate. © 2018 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.

Epidemiology. Tracking the human fallout from 'mad cow disease'.

PubMed

Balter, M

2000-09-01

A task force here has been studying cases of variant Creutzfeldt-Jakob disease (vCJD), an incurable malady of the brain and nervous system that has been linked to eating beef or other products from cattle infected with bovine spongiform encephalopathy or "mad cow disease." The team's goal is to find out just how the patients got infected and how many of them there may ultimately be. The number of confirmed or probable vCJD cases in the United Kingdom is still relatively small--a total of 80 as Science went to press--and recent estimates of the number of potential cases are lower than was once feared. Yet the task force's own recent results show that the incidence of vCJD is rising, and researchers remain determined to try to solve the riddles posed by vCJD.

Production of cattle lacking prion protein

PubMed Central

Richt, Jürgen A; Kasinathan, Poothappillai; Hamir, Amir N; Castilla, Joaquin; Sathiyaseelan, Thillai; Vargas, Francisco; Sathiyaseelan, Janaki; Wu, Hua; Matsushita, Hiroaki; Koster, Julie; Kato, Shinichiro; Ishida, Isao; Soto, Claudio; Robl, James M; Kuroiwa, Yoshimi

2010-01-01

Prion diseases are caused by propagation of misfolded forms of the normal cellular prion protein PrPC, such as PrPBSE in bovine spongiform encephalopathy (BSE) in cattle and PrPCJD in Creutzfeldt-Jakob disease (CJD) in humans1. Disruption of PrPC expression in mice, a species that does not naturally contract prion diseases, results in no apparent developmental abnormalities2–5. However, the impact of ablating PrPC function in natural host species of prion diseases is unknown. Here we report the generation and characterization of PrPC-deficient cattle produced by a sequential gene-targeting system6. At over 20 months of age, the cattle are clinically, physiologically, histopathologically, immunologically and reproductively normal. Brain tissue homogenates are resistant to prion propagation in vitro as assessed by protein misfolding cyclic amplification7. PrPC-deficient cattle may be a useful model for prion research and could provide industrial bovine products free of prion proteins. PMID:17195841

Accuracy of diagnosis criteria in patients with suspected diagnosis of sporadic Creutzfeldt-Jakob disease and detection of 14-3-3 protein, France, 1992 to 2009

PubMed Central

Peckeu, Laurene; Delasnerie-Lauprètre, Nicole; Brandel, Jean-Philippe; Salomon, Dominique; Sazdovitch, Véronique; Laplanche, Jean-Louis; Duyckaerts, Charles; Seilhean, Danielle; Haïk, Stéphane; Hauw, Jean-Jacques

2017-01-01

Diagnostic criteria of Creutzfeldt–Jakob disease (CJD), a rare and fatal transmissible nervous system disease with public health implications, are determined by clinical data, electroencephalogram (EEG), detection of 14-3-3 protein in cerebrospinal fluid (CSF), brain magnetic resonance imaging and prion protein gene examination. The specificity of protein 14-3-3 has been questioned. We reviewed data from 1,572 autopsied patients collected over an 18-year period (1992–2009) and assessed whether and how 14-3-3 detection impacted the diagnosis of sporadic CJD in France, and whether this led to the misdiagnosis of treatable disorders. 14-3-3 detection was introduced into diagnostic criteria for CJD in 1998. Diagnostic accuracy decreased from 92% for the 1992–1997 period to 85% for the 1998–2009 period. This was associated with positive detections of 14-3-3 in cases with negative EEG and alternative diagnosis at autopsy. Potentially treatable diseases were found in 163 patients (10.5%). This study confirms the usefulness of the recent modification of diagnosis criteria by the addition of the results of CSF real-time quaking-induced conversion, a method based on prion seed-induced misfolding and aggregation of recombinant prion protein substrate that has proven to be a highly specific test for diagnosis of sporadic CJD. PMID:29043964

Characterization of Variant Creutzfeldt-Jakob Disease Prions in Prion Protein-humanized Mice Carrying Distinct Codon 129 Genotypes*

PubMed Central

Takeuchi, Atsuko; Kobayashi, Atsushi; Ironside, James W.; Mohri, Shirou; Kitamoto, Tetsuyuki

2013-01-01

To date, all clinical variant Creutzfeldt-Jakob disease (vCJD) patients are homozygous for methionine at polymorphic codon 129 (129M/M) of the prion protein (PrP) gene. However, the appearance of asymptomatic secondary vCJD infection in individuals with a PRNP codon 129 genotype other than M/M and transmission studies using animal models have raised the concern that all humans might be susceptible to vCJD prions, especially via secondary infection. To reevaluate this possibility and to analyze in detail the transmission properties of vCJD prions to transgenic animals carrying distinct codon 129 genotype, we performed intracerebral inoculation of vCJD prions to humanized knock-in mice carrying all possible codon 129 genotypes (129M/M, 129M/V, or 129V/V). All humanized knock-in mouse lines were susceptible to vCJD infection, although the attack rate gradually decreased from 129M/M to 129M/V and to 129V/V. The amount of PrP deposition including florid/amyloid plaques in the brain also gradually decreased from 129M/M to 129M/V and to 129V/V. The biochemical properties of protease-resistant abnormal PrP in the brain and transmissibility of these humanized mouse-passaged vCJD prions upon subpassage into knock-in mice expressing bovine PrP were not affected by the codon 129 genotype. These results indicate that individuals with the 129V/V genotype may be more susceptible to secondary vCJD infection than expected and may lack the neuropathological characteristics observed in vCJD patients with the 129M/M genotype. Besides the molecular typing of protease-resistant PrP in the brain, transmission studies using knock-in mice carrying bovine PrP may aid the differential diagnosis of secondary vCJD infection, especially in individuals with the 129V/V genotype. PMID:23792955

Characterization of variant Creutzfeldt-Jakob disease prions in prion protein-humanized mice carrying distinct codon 129 genotypes.

PubMed

Takeuchi, Atsuko; Kobayashi, Atsushi; Ironside, James W; Mohri, Shirou; Kitamoto, Tetsuyuki

2013-07-26

To date, all clinical variant Creutzfeldt-Jakob disease (vCJD) patients are homozygous for methionine at polymorphic codon 129 (129M/M) of the prion protein (PrP) gene. However, the appearance of asymptomatic secondary vCJD infection in individuals with a PRNP codon 129 genotype other than M/M and transmission studies using animal models have raised the concern that all humans might be susceptible to vCJD prions, especially via secondary infection. To reevaluate this possibility and to analyze in detail the transmission properties of vCJD prions to transgenic animals carrying distinct codon 129 genotype, we performed intracerebral inoculation of vCJD prions to humanized knock-in mice carrying all possible codon 129 genotypes (129M/M, 129M/V, or 129V/V). All humanized knock-in mouse lines were susceptible to vCJD infection, although the attack rate gradually decreased from 129M/M to 129M/V and to 129V/V. The amount of PrP deposition including florid/amyloid plaques in the brain also gradually decreased from 129M/M to 129M/V and to 129V/V. The biochemical properties of protease-resistant abnormal PrP in the brain and transmissibility of these humanized mouse-passaged vCJD prions upon subpassage into knock-in mice expressing bovine PrP were not affected by the codon 129 genotype. These results indicate that individuals with the 129V/V genotype may be more susceptible to secondary vCJD infection than expected and may lack the neuropathological characteristics observed in vCJD patients with the 129M/M genotype. Besides the molecular typing of protease-resistant PrP in the brain, transmission studies using knock-in mice carrying bovine PrP may aid the differential diagnosis of secondary vCJD infection, especially in individuals with the 129V/V genotype.

Late-in-life surgery associated with Creutzfeldt-Jakob disease: a methodological outline for evidence-based guidance

PubMed Central

2013-01-01

Background There is increasing epidemiological evidence of etiological links between general surgery and sporadic Creutzfeldt-Jakob disease (sCJD) with long incubation periods. The purpose of this study was to identify specific surgical procedures potentially associated with sCJD to be targeted for preventive presurgical-intervention guidance. Results We propose a three-step clinical guidance outline where surgical procedures associated with sCJD clinical onset – potentially more contaminant - are taken into account. Data on hospital discharges and surgical procedures were obtained from Danish and Swedish national in-patient hospital registries for 167 sCJD cases, onset 1987–2003, and for 835 matched and 2,224 unmatched population controls. Surgery was allocated to different life-time periods as previously reported, and frequencies were compared using logistic regression analysis. In the year preceding clinical onset, persons with sCJD underwent a statistically significant higher number of minor surgical interventions (OR (95% CI): 17.50 (3.64-84.24)), transluminal endoscopies (OR: 2.73 (1.01–7.37)) and gastrointestinal operations (OR: 3.51 (1.21–10.19)) compared to matched controls. Surgical discharges clustered towards clinical onset. These differences increased during the clinical period, with statistically significant higher frequencies for both endoscopies and minor surgery (OR: 13.91 (5.87-32.95), and for main surgical procedures (OR: 2.10 (1.00-4.39)), particularly gastrointestinal surgery (OR: 6.00 (1.83-19.66)), and surgery contacting skeletal muscle. Comparisons with unmatched controls yielded similar results for neurosurgery in the clinical period (OR: 19.40 (2.22-168.34)). Conclusions These results suggest that some types of surgical procedures are associated with sCJD, after clinical onset or particularly just before onset. Selective planning of such surgery to minimize instrument/device contamination or quarantining might be feasible. Conditional to progress in sCJD etiological research, results are relevant for guidance development. PMID:23701872

Distinct pathological phenotypes of Creutzfeldt-Jakob disease in recipients of prion-contaminated growth hormone.

PubMed

Cali, Ignazio; Miller, Cathleen J; Parisi, Joseph E; Geschwind, Michael D; Gambetti, Pierluigi; Schonberger, Lawrence B

2015-06-25

The present study compares the clinical, pathological and molecular features of a United States (US) case of growth hormone (GH)-associated Creutzfeldt-Jakob disease (GH-CJD) (index case) to those of two earlier referred US cases of GH-CJD and one case of dura mater (d)-associated CJD (dCJD). All iatrogenic CJD (iCJD) subjects were methionine (M) homozygous at codon 129 (129MM) of the prion protein (PrP) gene and had scrapie prion protein (PrP(Sc)) type 1 (iCJDMM1). The index subject presented with ataxia, weight loss and changes in the sleep pattern about 38 years after the midpoint of GH treatment. Autopsy examination revealed a neuropathological phenotype reminiscent of both sCJDMV2-K (a sporadic CJD subtype in subjects methionine/valine heterozygous at codon 129 with PrP(Sc) type 2 and the presence of kuru plaques) and variant CJD (vCJD). The two earlier cases of GH-CJDMM1 and the one of dCJDMM1 were associated with neuropathological phenotypes that differed from that of the index case mainly because they lacked PrP plaques. The phenotype of the earlier GH-CJDMM1 cases shared several, but not all, characteristics with sCJDMM1, whereas dCJDMM1 was phenotypically indistinguishable from sCJDMM1. Two distinct groups of dCJDMM1 have also been described in Japan based on clinical features, the presence or absence of PrP plaques and distinct PK-resistant PrP(Sc) (resPrP(Sc)) electrophoretic mobilities. The resPrP(Sc) electrophoretic mobility was, however, identical in our GH-CJDMM1 and dCJDMM1 cases, and matched that of sCJDMM1. Our study shows that receipt of prion-contaminated GH can lead to a prion disease with molecular features (129MM and PrP(Sc) type 2) and phenotypic characteristics that differ from those of sporadic prion disease (sCJDMM1), a difference that may reflect adaptation of "heterologous" prion strains to the 129MM background.

Disease Burden of 32 Infectious Diseases in the Netherlands, 2007-2011

PubMed Central

Bouwknegt, Martijn; Kretzschmar, Mirjam E.; Mangen, Marie-Josée J.; Wallinga, Jacco; de Melker, Hester E.

2016-01-01

Background Infectious disease burden estimates provided by a composite health measure give a balanced view of the true impact of a disease on a population, allowing the relative impact of diseases that differ in severity and mortality to be monitored over time. This article presents the first national disease burden estimates for a comprehensive set of 32 infectious diseases in the Netherlands. Methods and Findings The average annual disease burden was computed for the period 2007–2011 for selected infectious diseases in the Netherlands using the disability-adjusted life years (DALY) measure. The pathogen- and incidence-based approach was adopted to quantify the burden due to both morbidity and premature mortality associated with all short and long-term consequences of infection. Natural history models, disease progression probabilities, disability weights, and other parameters were adapted from previous research. Annual incidence was obtained from statutory notification and other surveillance systems, which was corrected for under-ascertainment and under-reporting. The highest average annual disease burden was estimated for invasive pneumococcal disease (9444 DALYs/year; 95% uncertainty interval [UI]: 8911–9961) and influenza (8670 DALYs/year; 95% UI: 8468–8874), which represents 16% and 15% of the total burden of all 32 diseases, respectively. The remaining 30 diseases ranked by number of DALYs/year from high to low were: HIV infection, legionellosis, toxoplasmosis, chlamydia, campylobacteriosis, pertussis, tuberculosis, hepatitis C infection, Q fever, norovirus infection, salmonellosis, gonorrhoea, invasive meningococcal disease, hepatitis B infection, invasive Haemophilus influenzae infection, shigellosis, listeriosis, giardiasis, hepatitis A infection, infection with STEC O157, measles, cryptosporidiosis, syphilis, rabies, variant Creutzfeldt-Jakob disease, tetanus, mumps, rubella, diphtheria, and poliomyelitis. The very low burden for the latter five diseases can be attributed to the National Immunisation Programme. The average disease burden per individual varied from 0.2 (95% UI: 0.1–0.4) DALYs per 100 infections for giardiasis, to 5081 and 3581 (95% UI: 3540–3611) DALYs per 100 infections for rabies and variant Creutzfeldt-Jakob disease, respectively. Conclusions For guiding and supporting public health policy decisions regarding the prioritisation of interventions and preventive measures, estimates of disease burden and the comparison of burden between diseases can be informative. Although the collection of disease-specific parameters and estimation of incidence is a process subject to continuous improvement, the current study established a baseline for assessing the impact of future public health initiatives. PMID:27097024

Cooperative binding modes of Cu(II) in prion protein

NASA Astrophysics Data System (ADS)

Hodak, Miroslav; Chisnell, Robin; Lu, Wenchang; Bernholc, Jerry

2007-03-01

The misfolding of the prion protein, PrP, is responsible for a group of neurodegenerative diseases including mad cow disease and Creutzfeldt-Jakob disease. It is known that the PrP can efficiently bind copper ions; four high-affinity binding sites located in the octarepeat region of PrP are now well known. Recent experiments suggest that at low copper concentrations new binding modes, in which one copper ion is shared between two or more binding sites, are possible. Using our hybrid Thomas-Fermi/DFT computational scheme, which is well suited for simulations of biomolecules in solution, we investigate the geometries and energetics of two, three and four binding sites cooperatively binding one copper ion. These geometries are then used as inputs for classical molecular dynamics simulations. We find that copper binding affects the secondary structure of the PrP and that it stabilizes the unstructured (unfolded) part of the protein.

Canadian media representations of mad cow disease.

PubMed

Boyd, Amanda D; Jardine, Cynthia G; Driedger, S Michelle

2009-01-01

A Canadian case of bovine spongiform encephalopathy (BSE) or "mad cow disease" was confirmed in May, 2003. An in-depth content analysis of newspaper articles was conducted to understand the portrayal of BSE and variant Creutzfeldt-Jakob disease (vCJD) in the Canadian media. Articles in the "first 10 days" following the initial discovery of a cow with BSE in Canada on May 20, 2003, were examined based on the premise that these initial stories provide the major frames that dominate news media reporting of the same issue over time and multiple occurrences. Subsequent confirmed Canadian cases were similarly analyzed to determine if coverage changed in these later media articles. The results include a prominence of economic articles, de-emphasis of health aspects, and anchoring the Canadian outbreak to that of Britain's crisis. The variation in media representations between those in Canada and those documented in Britain are explored in this study.

Concentration-dependent Cu(II) binding to prion protein

NASA Astrophysics Data System (ADS)

Hodak, Miroslav; Lu, Wenchang; Bernholc, Jerry

2008-03-01

The prion protein plays a causative role in several neurodegenerative diseases, including mad cow disease in cattle and Creutzfeldt-Jakob disease in humans. The normal function of the prion protein is unknown, but it has been linked to its ability to bind copper ions. Experimental evidence suggests that copper can be bound in three distinct modes depending on its concentration, but only one of those binding modes has been fully characterized experimentally. Using a newly developed hybrid DFT/DFT method [1], which combines Kohn-Sham DFT with orbital-free DFT, we have examined all the binding modes and obtained their detailed binding geometries and copper ion binding energies. Our results also provide explanation for experiments, which have found that when the copper concentration increases the copper binding mode changes, surprisingly, from a stronger to a weaker one. Overall, our results indicate that prion protein can function as a copper buffer. 1. Hodak, Lu, Bernholc, JCP, in press.

A history of kuru.

PubMed

Alpers, Michael P

2007-01-01

Kuru is placed in its geographic and linguistic setting in the Eastern Highlands of Papua New Guinea. The epidemic of kuru has declined over the period 1957 to 2005 from more than 200 deaths a year to 1 or none. Since transmission of the kuru prion agent through the mortuary practice of transumption ceased by the early 1960s, the continuation of the epidemic into the present century demonstrates the long incubation periods that are possible in human prion diseases. Several histories of kuru are portrayed, from the different perspectives of the Fore people, of the scientists striving to elucidate the disease, of those engaged in research on prions, and of humans confronting the implications of kuru-like epidemics in the remote past. Kuru has connections to bovine spongiform encephalopathy through intraspecies recycling. The influence of host genetics on the incubation period in kuru may help to predict the shape of the still ongoing epidemic of variant Creutzfeldt-Jakob disease.

[Disease concept of the slow virus infection].

PubMed

Takasu, Toshiaki

2007-08-01

This article gives a brief history of the terminology of slow virus infection, the conceptual change that occurred in it, the features common to slow infection and the current concept of slow virus infection. Björn Sigurdsson from the field of veterinary medicine proposed slow virus infection as unique mode of infection in 1954. Its initial concept was remodeled along with the general acceptance of prion theory of sheep scrapie that was proposed in 1982. The features common to slow infection include very long latency, unanimous poor prognosis, central nervous system involvement, etc. Currently the slow infection comprises those caused by slow conventional viruses that is the slow virus infection (for example subacute sclerosing panencephalitis and progressive multifocal encephalopathy in human and visna-maedi in sheep) and prion diseases (for example kuru, Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome in human, scrapie and bovine spongiform encephalopathy).

Understanding amyloid aggregation by statistical analysis of atomic force microscopy images

NASA Astrophysics Data System (ADS)

Adamcik, Jozef; Jung, Jin-Mi; Flakowski, Jérôme; de Los Rios, Paolo; Dietler, Giovanni; Mezzenga, Raffaele

2010-06-01

The aggregation of proteins is central to many aspects of daily life, including food processing, blood coagulation, eye cataract formation disease and prion-related neurodegenerative infections. However, the physical mechanisms responsible for amyloidosis-the irreversible fibril formation of various proteins that is linked to disorders such as Alzheimer's, Creutzfeldt-Jakob and Huntington's diseases-have not yet been fully elucidated. Here, we show that different stages of amyloid aggregation can be examined by performing a statistical polymer physics analysis of single-molecule atomic force microscopy images of heat-denatured β-lactoglobulin fibrils. The atomic force microscopy analysis, supported by theoretical arguments, reveals that the fibrils have a multistranded helical shape with twisted ribbon-like structures. Our results also indicate a possible general model for amyloid fibril assembly and illustrate the potential of this approach for investigating fibrillar systems.

Transmission Characteristics of Variably Protease-Sensitive Prionopathy

PubMed Central

Notari, Silvio; Xiao, Xiangzhu; Espinosa, Juan Carlos; Cohen, Yvonne; Qing, Liuting; Aguilar-Calvo, Patricia; Kofskey, Diane; Cali, Ignazio; Cracco, Laura; Kong, Qingzhong; Torres, Juan Maria

2014-01-01

Variably protease-sensitive prionopathy (VPSPr), a recently identified and seemingly sporadic human prion disease, is distinct from Creutzfeldt-Jakob disease (CJD) but shares features of Gerstmann-Sträussler-Scheinker disease (GSS). However, contrary to exclusively inherited GSS, no prion protein (PrP) gene variations have been detected in VPSPr, suggesting that VPSPr might be the long-sought sporadic form of GSS. The VPSPr atypical features raised the issue of transmissibility, a prototypical property of prion diseases. We inoculated VPSPr brain homogenate into transgenic mice expressing various levels of human PrP (PrPC). On first passage, 54% of challenged mice showed histopathologic lesions, and 34% harbored abnormal PrP similar to that of VPSPr. Surprisingly, no prion disease was detected on second passage. We concluded that VPSPr is transmissible; thus, it is an authentic prion disease. However, we speculate that normal human PrPC is not an efficient conversion substrate (or mouse brain not a favorable environment) and therefore cannot sustain replication beyond the first passage. PMID:25418590

The prion protein protease sensitivity, stability and seeding activity in variably protease sensitive prionopathy brain tissue suggests molecular overlaps with sporadic Creutzfeldt-Jakob disease.

PubMed

Peden, Alexander H; Sarode, Deep P; Mulholland, Carl R; Barria, Marcelo A; Ritchie, Diane L; Ironside, James W; Head, Mark W

2014-10-21

Variably protease sensitive prionopathy (VPSPr) is a recently described, sporadic human prion disease that is pathologically and biochemically distinct from the currently recognised sporadic Creutzfeldt-Jakob disease (sCJD) subtypes. The defining biochemical features of the abnormal form of the prion protein (PrPSc) in VPSPr are increased sensitivity to proteolysis and the presence of an N- and C-terminally cleaved ~8 kDa protease resistant PrPSc (PrPres) fragment. The biochemical and neuropathological profile of VPSPr has been proposed to resemble either Gerstmann-Sträussler-Scheinker syndrome (GSS) or familial CJD with the PRNP-V180I mutation. However, in some cases of VPSPr two protease resistant bands have been observed in Western blots that co-migrate with those of type 2 PrPres, suggesting that a proportion of the PrPSc present in VPSPr has properties similar to those of sCJD. Here, we have used conformation dependent immunoassay to confirm the presence of PrPSc in VPSPr that is more protease sensitive compared with sCJD. However, CDI also shows that a proportion of PrPSc in VPSPr resists PK digestion of its C-terminus, distinguishing it from GSS associated with ~8 kDa PrPres, and showing similarity to sCJD. Intensive investigation of a single VPSPr case with frozen tissue from multiple brain regions shows a broad, region-specific spectrum of protease sensitivity and differential stability of PrPSc in the absence of PK treatment. Finally, using protein misfolding cyclic amplification and real-time quaking induced conversion, we show that VPSPr PrPSc has the potential to seed conversion in vitro and that seeding activity is dispersed through a broad range of aggregate sizes. We further propose that seeding activity is associated with the ~19 and ~23 kDa PrPres rather than the ~8 kDa fragment. Therefore, PrPSc in VPSPr is heterogeneous in terms of protease sensitivity and stability to denaturation with the chaotrope GdnHCl and includes a proportion with similar properties to that found in sCJD.

A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk.

PubMed

Sanchez-Juan, Pascual; Bishop, Matthew T; Kovacs, Gabor G; Calero, Miguel; Aulchenko, Yurii S; Ladogana, Anna; Boyd, Alison; Lewis, Victoria; Ponto, Claudia; Calero, Olga; Poleggi, Anna; Carracedo, Ángel; van der Lee, Sven J; Ströbel, Thomas; Rivadeneira, Fernando; Hofman, Albert; Haïk, Stéphane; Combarros, Onofre; Berciano, José; Uitterlinden, Andre G; Collins, Steven J; Budka, Herbert; Brandel, Jean-Philippe; Laplanche, Jean Louis; Pocchiari, Maurizio; Zerr, Inga; Knight, Richard S G; Will, Robert G; van Duijn, Cornelia M

2014-01-01

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.

Emergence of two prion subtypes in ovine PrP transgenic mice infected with human MM2-cortical Creutzfeldt-Jakob disease prions.

PubMed

Chapuis, Jérôme; Moudjou, Mohammed; Reine, Fabienne; Herzog, Laetitia; Jaumain, Emilie; Chapuis, Céline; Quadrio, Isabelle; Boulliat, Jacques; Perret-Liaudet, Armand; Dron, Michel; Laude, Hubert; Rezaei, Human; Béringue, Vincent

2016-02-05

Mammalian prions are proteinaceous pathogens responsible for a broad range of fatal neurodegenerative diseases in humans and animals. These diseases can occur spontaneously, such as Creutzfeldt-Jakob disease (CJD) in humans, or be acquired or inherited. Prions are primarily formed of macromolecular assemblies of the disease-associated prion protein PrP(Sc), a misfolded isoform of the host-encoded prion protein PrP(C). Within defined host-species, prions can exist as conformational variants or strains. Based on both the M/V polymorphism at codon 129 of PrP and the electrophoretic signature of PrP(Sc) in the brain, sporadic CJD is classified in different subtypes, which may encode different strains. A transmission barrier, the mechanism of which remains unknown, limits prion cross-species propagation. To adapt to the new host, prions have the capacity to 'mutate' conformationally, leading to the emergence of a variant with new biological properties. Here, we transmitted experimentally one rare subtype of human CJD, designated cortical MM2 (129 MM with type 2 PrP(Sc)), to transgenic mice overexpressing either human or the VRQ allele of ovine PrP(C). In marked contrast with the reported absence of transmission to knock-in mice expressing physiological levels of human PrP, this subtype transmitted faithfully to mice overexpressing human PrP, and exhibited unique strain features. Onto the ovine PrP sequence, the cortical MM2 subtype abruptly evolved on second passage, thereby allowing emergence of a pair of strain variants with distinct PrP(Sc) biochemical characteristics and differing tropism for the central and lymphoid tissues. These two strain components exhibited remarkably distinct replicative properties in cell-free amplification assay, allowing the 'physical' cloning of the minor, lymphotropic component, and subsequent isolation in ovine PrP mice and RK13 cells. Here, we provide in-depth assessment of the transmissibility and evolution of one rare subtype of sporadic CJD upon homologous and heterologous transmission. The notion that the environment or matrix where replication is occurring is key to the selection and preferential amplification of prion substrain components raises new questions on the determinants of prion replication within and between species. These data also further interrogate on the interplay between animal and human prions.

Iatrogenic Creutzfeldt-Jakob disease with Amyloid-β pathology: an international study.

PubMed

Cali, Ignazio; Cohen, Mark L; Haїk, Stéphane; Parchi, Piero; Giaccone, Giorgio; Collins, Steven J; Kofskey, Diane; Wang, Han; McLean, Catriona A; Brandel, Jean-Philippe; Privat, Nicolas; Sazdovitch, Véronique; Duyckaerts, Charles; Kitamoto, Tetsuyuki; Belay, Ermias D; Maddox, Ryan A; Tagliavini, Fabrizio; Pocchiari, Maurizio; Leschek, Ellen; Appleby, Brian S; Safar, Jiri G; Schonberger, Lawrence B; Gambetti, Pierluigi

2018-01-08

The presence of pathology related to the deposition of amyloid-β (Aβ) has been recently reported in iatrogenic Creutzfeldt-Jakob disease (iCJD) acquired from inoculation of growth hormone (GH) extracted from human cadaveric pituitary gland or use of cadaveric dura mater (DM) grafts.To investigate this phenomenon further, a cohort of 27 iCJD cases - 21 with adequate number of histopathological sections - originating from Australia, France, Italy, and the Unites States, were examined by immunohistochemistry, amyloid staining, and Western blot analysis of the scrapie prion protein (PrP Sc ), and compared with age-group matched cases of sporadic CJD (sCJD), Alzheimer disease (AD) or free of neurodegenerative diseases (non-ND).Cases of iCJD and sCJD shared similar profiles of proteinase K-resistant PrP Sc with the exception of iCJD harboring the "MMi" phenotype. Cerebral amyloid angiopathy (CAA), either associated with, or free of, Thioflavin S-positive amyloid core plaques (CP), was observed in 52% of 21 cases of iCJD, which comprised 37.5% and 61.5% of the cases of GH- and DM-iCJD, respectively. If only cases younger than 54 years were considered, Aβ pathology affected 41%, 2% and 0% of iCJD, sCJD and non-ND, respectively. Despite the patients' younger age CAA was more severe in iCJD than sCJD, while Aβ diffuse plaques, in absence of Aβ CP, populated one third of sCJD. Aβ pathology was by far most severe in AD. Tau pathology was scanty in iCJD and sCJD.In conclusion, (i) despite the divergences in the use of cadaveric GH and DM products, our cases combined with previous studies showed remarkably similar iCJD and Aβ phenotypes indicating that the occurrence of Aβ pathology in iCJD is a widespread phenomenon, (ii) CAA emerges as the hallmark of the Aβ phenotype in iCJD since it is observed in nearly 90% of all iCJD with Aβ pathology reported to date including ours, and it is shared by GH- and DM-iCJD, (iii) although the contributions to Aβ pathology of other factors, including GH deficiency, cannot be discounted, our findings increase the mounting evidence that this pathology is acquired by a mechanism resembling that of prion diseases.

Effects on instruments of the World Health Organization--recommended protocols for decontamination after possible exposure to transmissible spongiform encephalopathy-contaminated tissue.

PubMed

Brown, Stanley A; Merritt, Katharine; Woods, Terry O; Busick, Deanna N

2005-01-15

It has been recommended by the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) that rigorous decontamination protocols be used on surgical instruments that have been exposed to tissue possibly contaminated with Creutzfeldt-Jakob disease (CJD). This study was designed to examine the effects of these protocols on various types of surgical instruments. The most important conclusions are: (1) autoclaving in 1N NaOH will cause darkening of some instruments; (2) soaking in 1N NaOH at room temperature damages carbon steel but not stainless steel or titanium; (3) soaking in chlorine bleach will badly corrode gold-plated instruments and will damage some, but not all, stainless-steel instruments, especially welded and soldered joints. Damage became apparent after the first exposure and therefore long tests are not necessary to establish which instruments will be damaged. Copyright 2004 Wiley Periodicals, Inc.

Structure-Based Prediction of Unstable Regions in Proteins: Applications to Protein Misfolding Diseases

NASA Astrophysics Data System (ADS)

Guest, Will; Cashman, Neil; Plotkin, Steven

2009-03-01

Protein misfolding is a necessary step in the pathogenesis of many diseases, including Creutzfeldt-Jakob disease (CJD) and familial amyotrophic lateral sclerosis (fALS). Identifying unstable structural elements in their causative proteins elucidates the early events of misfolding and presents targets for inhibition of the disease process. An algorithm was developed to calculate the Gibbs free energy of unfolding for all sequence-contiguous regions of a protein using three methods to parameterize energy changes: a modified G=o model, changes in solvent-accessible surface area, and solution of the Poisson-Boltzmann equation. The entropic effects of disulfide bonds and post-translational modifications are treated analytically. It incorporates a novel method for finding local dielectric constants inside a protein to accurately handle charge effects. We have predicted the unstable parts of prion protein and superoxide dismutase 1, the proteins involved in CJD and fALS respectively, and have used these regions as epitopes to prepare antibodies that are specific to the misfolded conformation and show promise as therapeutic agents.

Identifying Unstable Regions of Proteins Involved in Misfolding Diseases

NASA Astrophysics Data System (ADS)

Guest, Will; Cashman, Neil; Plotkin, Steven

2009-05-01

Protein misfolding is a necessary step in the pathogenesis of many diseases, including Creutzfeldt-Jakob disease (CJD) and familial amyotrophic lateral sclerosis (fALS). Identifying unstable structural elements in their causative proteins elucidates the early events of misfolding and presents targets for inhibition of the disease process. An algorithm was developed to calculate the Gibbs free energy of unfolding for all sequence-contiguous regions of a protein using three methods to parameterize energy changes: a modified G=o model, changes in solvent-accessible surface area, and all-atoms molecular dynamics. The entropic effects of disulfide bonds and post-translational modifications are treated analytically. It incorporates a novel method for finding local dielectric constants inside a protein to accurately handle charge effects. We have predicted the unstable parts of prion protein and superoxide dismutase 1, the proteins involved in CJD and fALS respectively, and have used these regions as epitopes to prepare antibodies that are specific to the misfolded conformation and show promise as therapeutic agents.

Neurological adverse events associated with vaccination.

PubMed

Piyasirisilp, Sucheep; Hemachudha, Thiravat

2002-06-01

Public tolerance to adverse reactions is minimal. Several reporting systems have been established to monitor adverse events following immunization. The present review summarizes data on neurologic complications following vaccination, and provides evidence that indicates whether they were directly associated with the vaccines. These complications include autism (measles vaccine), multiple sclerosis (hepatitis B vaccine), meningoencephalitis (Japanese encephalitis vaccine), Guillain-Barré syndrome and giant cell arteritis (influenza vaccine), and reactions after exposure to animal rabies vaccine. Seizures and hypotonic/hyporesponsive episodes following pertussis vaccination and potential risks associated with varicella vaccination, as well as vaccine-associated paralytic poliomyelitis following oral poliovirus vaccination, are also described. In addition, claims that complications are caused by adjuvants, preservatives and contaminants [i.e. macrophagic myofasciitis (aluminium), neurotoxicity (thimerosal), and new variant Creutzfeldt-Jakob disease (bovine-derived materials)] are discussed.

Molecular modelling indicates that the pathological conformations of prion proteins might be beta-helical.

PubMed Central

Downing, D T; Lazo, N D

1999-01-01

Creutzfeldt-Jakob disease, kuru, scrapie and bovine spongiform encephalopathy are diseases of the mammalian central nervous system that involve the conversion of a cellular protein into an insoluble extracellular isoform. Spectroscopic studies have shown that the precursor protein contains mainly alpha-helical and random-coil conformations, whereas the prion isoform is largely in the beta conformation. The pathogenic prion is resistant to denaturation and protease digestion and can promote the conversion of the precursor protein to the pathogenic form. These properties have yet to be explained in terms of the structural conformations of the proteins. In the present study, molecular modelling showed that prion proteins could adopt the beta-helical conformation, which has been established for a number of fibrous proteins and has been suggested previously as the basis of amyloid fibrils. The beta-helical conformation provides explanations for the biophysical and biochemical stability of prions, their ability to form templates for the transmission of pathological conformation, and the existence of phenotypical strains of the prion diseases. PMID:10510313

The expanding universe of prion diseases.

PubMed

Watts, Joel C; Balachandran, Aru; Westaway, David

2006-03-01

Prions cause fatal and transmissible neurodegenerative disease. These etiological infectious agents are formed in greater part from a misfolded cell-surface protein called PrP(C). Several mammalian species are affected by the diseases, and in the case of "mad cow disease" (BSE) the agent has a tropism for humans, with negative consequences for agribusiness and public health. Unfortunately, the known universe of prion diseases is expanding. At least four novel prion diseases--including human diseases variant Creutzfeldt-Jakob disease (vCJD) and sporadic fatal insomnia (sFI), bovine amyloidotic spongiform encephalopathy (BASE), and Nor98 of sheep--have been identified in the last ten years, and chronic wasting disease (CWD) of North American deer (Odocoileus Specis) and Rocky Mountain elk (Cervus elaphus nelsoni) is undergoing a dramatic spread across North America. While amplification (BSE) and dissemination (CWD, commercial sourcing of cervids from the wild and movement of farmed elk) can be attributed to human activity, the origins of emergent prion diseases cannot always be laid at the door of humankind. Instead, the continued appearance of new outbreaks in the form of "sporadic" disease may be an inevitable outcome in a situation where the replicating pathogen is host-encoded.

Copper attachment to a non-octarepeat site in prion protein

NASA Astrophysics Data System (ADS)

Hodak, Miroslav; Bernholc, Jerry

2010-03-01

Prion protein, PrP, plays a causative role in several neurodegenerative diseases, including mad cow disease in cattle and Creutzfeldt-Jakob disease in humans. The PrP is known to efficiently bind copper ions and this ability has been linked to its function. PrP contains up to six binding sites, four of which are located in the so-called octarepeat region and are now well known. The binding sites outside this region are still largely undetermined, despite evidence of their relevance to prion diseases. Using a hybrid DFT/DFT, which combines Kohn-Sham DFT with orbital-free DFT to achieve accurate and efficient description of solvent effects in ab initio calculations, we have investigated copper attachment to the sequence GGGTH, which represents the copper binding site located at His96. We have considered both NNNN and NNNO types of copper coordination, as suggested by experiments. Our calculations have determined the geometry of copper attachment site and its energetics. Comparison to the already known binding sites provides insight into the process of copper uptake in PrP.

Genotype-dependent Molecular Evolution of Sheep Bovine Spongiform Encephalopathy (BSE) Prions in Vitro Affects Their Zoonotic Potential*

PubMed Central

Krejciova, Zuzana; Barria, Marcelo A.; Jones, Michael; Ironside, James W.; Jeffrey, Martin; González, Lorenzo; Head, Mark W.

2014-01-01

Prion diseases are rare fatal neurological conditions of humans and animals, one of which (variant Creutzfeldt-Jakob disease) is known to be a zoonotic form of the cattle disease bovine spongiform encephalopathy (BSE). What makes one animal prion disease zoonotic and others not is poorly understood, but it appears to involve compatibility between the prion strain and the host prion protein sequence. Concerns have been raised that the United Kingdom sheep flock may have been exposed to BSE early in the cattle BSE epidemic and that serial BSE transmission in sheep might have resulted in adaptation of the agent, which may have come to phenotypically resemble scrapie while maintaining its pathogenicity for humans. We have modeled this scenario in vitro. Extrapolation from our results suggests that if BSE were to infect sheep in the field it may, with time and in some sheep genotypes, become scrapie-like at the molecular level. However, the results also suggest that if BSE in sheep were to come to resemble scrapie it would lose its ability to affect humans. PMID:25100723

Human stem cell-derived astrocytes replicate human prions in a PRNP genotype-dependent manner.

PubMed

Krejciova, Zuzana; Alibhai, James; Zhao, Chen; Krencik, Robert; Rzechorzek, Nina M; Ullian, Erik M; Manson, Jean; Ironside, James W; Head, Mark W; Chandran, Siddharthan

2017-12-04

Prions are infectious agents that cause neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD). The absence of a human cell culture model that replicates human prions has hampered prion disease research for decades. In this paper, we show that astrocytes derived from human induced pluripotent stem cells (iPSCs) support the replication of prions from brain samples of CJD patients. For experimental exposure of astrocytes to variant CJD (vCJD), the kinetics of prion replication occur in a prion protein codon 129 genotype-dependent manner, reflecting the genotype-dependent susceptibility to clinical vCJD found in patients. Furthermore, iPSC-derived astrocytes can replicate prions associated with the major sporadic CJD strains found in human patients. Lastly, we demonstrate the subpassage of prions from infected to naive astrocyte cultures, indicating the generation of prion infectivity in vitro. Our study addresses a long-standing gap in the repertoire of human prion disease research, providing a new in vitro system for accelerated mechanistic studies and drug discovery. © 2017 Krejciova et al.

The Expanding Universe of Prion Diseases

PubMed Central

Watts, Joel C; Balachandran, Aru; Westaway, David

2006-01-01

Prions cause fatal and transmissible neurodegenerative disease. These etiological infectious agents are formed in greater part from a misfolded cell-surface protein called PrPC. Several mammalian species are affected by the diseases, and in the case of “mad cow disease” (BSE) the agent has a tropism for humans, with negative consequences for agribusiness and public health. Unfortunately, the known universe of prion diseases is expanding. At least four novel prion diseases—including human diseases variant Creutzfeldt-Jakob disease (vCJD) and sporadic fatal insomnia (sFI), bovine amyloidotic spongiform encephalopathy (BASE), and Nor98 of sheep—have been identified in the last ten years, and chronic wasting disease (CWD) of North American deer (Odocoileus Specis) and Rocky Mountain elk (Cervus elaphus nelsoni) is undergoing a dramatic spread across North America. While amplification (BSE) and dissemination (CWD, commercial sourcing of cervids from the wild and movement of farmed elk) can be attributed to human activity, the origins of emergent prion diseases cannot always be laid at the door of humankind. Instead, the continued appearance of new outbreaks in the form of “sporadic” disease may be an inevitable outcome in a situation where the replicating pathogen is host-encoded. PMID:16609731

Variably Protease-Sensitive Prionopathy, a Unique Prion Variant with Inefficient Transmission Properties

PubMed Central

Diack, Abigail B.; Ritchie, Diane L.; Peden, Alexander H.; Brown, Deborah; Boyle, Aileen; Morabito, Laura; Maclennan, David; Burgoyne, Paul; Jansen, Casper; Knight, Richard S.; Piccardo, Pedro; Ironside, James W.

2014-01-01

Variably protease-sensitive prionopathy (VPSPr) can occur in persons of all codon 129 genotypes in the human prion protein gene (PRNP) and is characterized by a unique biochemical profile when compared with other human prion diseases. We investigated transmission properties of VPSPr by inoculating transgenic mice expressing human PRNP with brain tissue from 2 persons with the valine-homozygous (VV) and 1 with the heterozygous methionine/valine codon 129 genotype. No clinical signs or vacuolar pathology were observed in any inoculated mice. Small deposits of prion protein accumulated in the brains of inoculated mice after challenge with brain material from VV VPSPr patients. Some of these deposits resembled microplaques that occur in the brains of VPSPr patients. Comparison of these transmission properties with those of sporadic Creutzfeldt-Jakob disease in the same lines of mice indicated that VPSPr has distinct biological properties. Moreover, we established that VPSPr has limited potential for human-to-human transmission. PMID:25418327

John H. Dillon Medal Talk: Protein Fibrils, Polymer Physics: Encounter at the Nanoscale

NASA Astrophysics Data System (ADS)

Mezzenga, Raffaele

2011-03-01

Aggregation of proteins is central to many aspects of daily life, ranging from blood coagulation, to eye cataract formation disease, food processing, or neurodegenerative infections. In particular, the physical mechanisms responsible for amyloidosis, the irreversible fibril formation of various proteins implicated in protein misfolding disorders such as Alzheimer, Creutzfeldt-Jakob or Huntington's diseases, have not yet been fully elucidated. In this talk I will discuss how polymer physics and colloidal science concepts can be used to reveal very useful information on the formation, structure and properties of amyloid protein fibrils. I will discuss their physical properties at various length scales, from their collective liquid crystalline behavior in solution to their structural features at the single molecule length scale and show how polymer science notions can shed a new light on these interesting systems. 1) ``Understanding amyloid aggregation by statistical analysis of atomic force microscopy images'' J. Adamcik, J.-M. Jung, J. Flakowski, P. De Los Rios, G. Dietler and R. Mezzenga, Nature nanotechnology, 5, 423 (2010)

Biology and Genetics of Prions Causing Neurodegeneration

PubMed Central

Prusiner, Stanley B.

2014-01-01

Prions are proteins that acquire alternative conformations that become self-propagating. Transformation of proteins into prions is generally accompanied by an increase in β-sheet structure and a propensity to aggregate into oligomers. Some prions are beneficial and perform cellular functions, whereas others cause neurodegeneration. In mammals, more than a dozen proteins that become prions have been identified and a similar number has been found in fungi. In both mammals and fungi, variations in the prion conformation encipher the biological properties of distinct prion strains. Increasing evidence argues that prions cause many neurodegenerative diseases (NDs), including Alzheimer’s, Parkinson’s, Creutzfeldt-Jakob, and Lou Gehrig’s diseases, as well as the tauopathies. The majority of NDs are sporadic, and 10% to 20% are inherited. The late onset of heritable NDs, like their sporadic counterparts, may reflect the stochastic nature of prion formation; the pathogenesis of such illnesses seems to require prion accumulation to exceed some critical threshold before neurological dysfunction manifests. PMID:24274755

The molecular epidemiology of variant CJD

PubMed Central

Mackay, Graham A; Knight, Richard SG; Ironside, James W

2011-01-01

The emergence of the novel prion diseases bovine spongiform encephalopathy (BSE) and, subsequently, variant Creutzfeldt-Jakob disease (vCJD) in epidemic forms has attracted much scientific attention. The oral transmission of these disorders, the causative relationship of vCJD to BSE and the resistance of the transmissible agents in both disorders to conventional forms of decontamination has caused great public health concern. The size of the still emerging vCJD epidemic is thankfully much lower than some early published estimates. This paper reviews current knowledge of the factors that influence the development of vCJD: the properties of the infectious agent; the route of inoculation and individual susceptibility factors. The current epidemiological data are reviewed, along with relevant animal transmission studies. In terms of genetic susceptibility, the best characterised is the common single nucleotide polymorphism at codon 129 of prion protein gene. Current biomarkers and future areas of research will be discussed. These issues are important in informing precautionary measures and the ongoing monitoring of vCJD. PMID:21915360

[Rules and regulations concerning contact lens-related infection].

PubMed

Feys, J

2004-04-01

Contact lens-related infectious keratitis is a potentially sight-threatening complication. Bacterial keratitis, mostly due to Gram-negative bacteria, is associated with poor lens hygiene, overnight wear, and contaminated lens care solutions. Contamination of the lens storage case may cause fungal keratitis. Acanthamoeba infection is related to the use of tap water or swimming while wearing soft lenses. Viruses are of less concern among contact lens wearers. Possible transmission of Creutzfeldt-Jakob disease by multi-patient trial lenses must be taken in account. To minimize these risk factors, regulations are applied at various levels: CE marking of contact lenses and care products as they are medical devices; contact lens fitting only by health care professionals; distribution of contact lenses by opticians and lens care solutions by opticians and pharmacists; hygienic management of trial lenses following official recommendations. Contact lens-related keratitis must be reported to health care Authorities.

Cling film as a barrier against CJD in corneal contact A-scan ultrasonography.

PubMed

Rani, Asha; Dunne, Mark C M; Barnes, Derek A

2003-01-01

To determine the validity of covering a corneal contact transducer probe with cling film as protection against the transmission of Creutzfeldt-Jakob disease (CJD). The anterior chamber depth, lens thickness and vitreous chamber depth of the right eyes of 10 subjects was recorded, under cycloplegia, with and without cling film covering over the transducer probe of a Storz Omega Compu-scan Biometric Ruler. Measurements were repeated on two occasions. Cling film covering did not influence bias or repeatability. Although the 95% limits of agreement between measurements made with and without cling film covering tended to exceed the intrasessional repeatability, they did not exceed the intersessional repeatability of measurements taken without cling film. The results support the use of cling film as a disposable covering for corneal contact A-scan ultrasonography to avoid the risk of spreading CJD from one subject to another.

The influence of PRNP polymorphisms on human prion disease susceptibility: an update.

PubMed

Kobayashi, Atsushi; Teruya, Kenta; Matsuura, Yuichi; Shirai, Tsuyoshi; Nakamura, Yoshikazu; Yamada, Masahito; Mizusawa, Hidehiro; Mohri, Shirou; Kitamoto, Tetsuyuki

2015-08-01

Two normally occurring polymorphisms of the human PRNP gene, methionine (M)/valine (V) at codon 129 and glutamic acid (E)/lysine (K) at codon 219, can affect the susceptibility to prion diseases. It has long been recognized that 129M/M homozygotes are overrepresented in sporadic Creutzfeldt-Jakob disease (CJD) patients and variant CJD patients, whereas 219E/K heterozygotes are absent in sporadic CJD patients. In addition to these pioneering findings, recent progress in experimental transmission studies and worldwide surveillance of prion diseases have identified novel relationships between the PRNP polymorphisms and the prion disease susceptibility. For example, although 219E/K heterozygosity confers resistance against the development of sporadic CJD, this genotype is not entirely protective against acquired forms (iatrogenic CJD and variant CJD) or genetic forms (genetic CJD and Gerstmann-Sträussler-Scheinker syndrome) of prion diseases. In addition, 129M/V heterozygotes predispose to genetic CJD caused by a pathogenic PRNP mutation at codon 180. These findings show that the effects of the PRNP polymorphisms may be more complicated than previously thought. This review aims to summarize recent advances in our knowledge about the influence of the PRNP polymorphisms on the prion disease susceptibility.

Creutzfeldt-Jakob disease and mad cows: lessons learnt from yeast cells.

PubMed

Hofmann, J; Wolf, H; Grassmann, A; Arndt, V; Graham, J; Vorberg, I

2012-01-24

Transmissible spongiform encephalopathies are fatal neurodegenerative diseases that affect mammals including humans. The proteinaceous nature of the infectious agent, the prion, and its propagation, challenge established dogmas in biology. It is now widely accepted that prion diseases are caused by unconventional agents principally composed of a misfolded host-encoded protein, PrP. Surprisingly, major break-throughs in prion research came from studies on functionally unrelated proteins in yeast and filamentous fungi. Aggregates composed of these proteins act as epigenetic elements of inheritance that can propagate their alternative states by a conformational switch into an ordered ß-sheet rich polymer just like mammalian prions. Since their discovery prions of lower eukaryotes have provided invaluable insights into all aspects of prion biogenesis. Importantly, yeast prions provide proof-of-principle that distinct protein conformers can be infectious and can serve as genetic elements that have the capacity to encipher strain specific information. As a powerful and tractable model system, yeast prions will continue to increase our understanding of prion-host cell interaction and potential mechanisms of protein-based epigenetic inheritance.

Superoxide dismutase activity of Cu-bound prion protein

NASA Astrophysics Data System (ADS)

Hodak, Miroslav; Lu, Wenchang; Bernholc, Jerry

2009-03-01

Misfolding of the prion protein, PrP, has been linked to a group of neurodegenerative diseases, including the mad cow disease in cattle and the Creutzfeldt-Jakob disease in humans. The normal function of PrP is still unknown, but it was found that the PrP can efficiently bind Cu(II) ions. Early experiments suggested that Cu-PrP complex possesses significant superoxide dismutase (SOD) activity, but later experiments failed to confirm it and at present this issue remains unresolved. Using a recently developed hybrid DFT/DFT method, which combines Kohn-Sham DFT for the solute and its first solvation shells with orbital-free DFT for the remainder of the solvent, we have investigated SOD activity of PrP. The PrP is capable of incorporating Cu(II) ions in several binding modes and our calculations find that each mode has a different SOD activity. The highest activity found is comparable to those of well-known SOD proteins, suggesting that the conflicting experimental results may be due to different bindings of Cu(II) in those experiments.

Determination of neuronal antibodies in suspected and definite Creutzfeldt-Jakob disease.

PubMed

Grau-Rivera, Oriol; Sánchez-Valle, Raquel; Saiz, Albert; Molinuevo, José Luis; Bernabé, Reyes; Munteis, Elvira; Pujadas, Francesc; Salvador, Antoni; Saura, Júlia; Ugarte, Antonio; Titulaer, Maarten; Dalmau, Josep; Graus, Francesc

2014-01-01

Creutzfeldt-Jakob disease (CJD) and autoimmune encephalitis with antibodies against neuronal surface antigens (NSA-abs) may present with similar clinical features. Establishing the correct diagnosis has practical implications in the management of care for these patients. To determine the frequency of NSA-abs in the cerebrospinal fluid of patients with suspected CJD and in patients with pathologically confirmed (ie, definite) CJD. A mixed prospective (suspected) and retrospective (definite) CJD cohort study was conducted in a reference center for detection of NSA-abs. The population included 346 patients with suspected CJD and 49 patients with definite CJD. Analysis of NSA-abs in cerebrospinal fluid with brain immunohistochemistry optimized for cell-surface antigens was performed. Positive cases in the suspected CJD group were further studied for antigen specificity using cell-based assays. All definite CJD cases were comprehensively tested for NSA-abs, with cell-based assays used for leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), N-methyl-d-aspartate (NMDA), and glycine (GlY) receptors. Neuronal surface antigens were detected in 6 of 346 patients (1.7%) with rapid neurologic deterioration suggestive of CJD. None of these 6 patients fulfilled the diagnostic criteria for probable or possible CJD. The target antigens included CASPR2, LGI1, NMDAR, aquaporin 4, Tr (DNER [δ/notch-like epidermal growth factor-related receptor]), and an unknown protein. Four of the patients developed rapidly progressive dementia, and the other 2 patients had cerebellar ataxia or seizures that were initially considered to be myoclonus without cognitive decline. The patient with Tr-abs had a positive 14-3-3 test result. Small cell lung carcinoma was diagnosed in the patient with antibodies against an unknown antigen. All patients improved or stabilized after appropriate treatment. None of the 49 patients with definite CJD had NSA-abs. A low, but clinically relevant, number of patients with suspected CJD had potentially treatable disorders associated with NSA-abs. In contrast, none of 49 patients with definite CJD had NSA-abs, including NMDAR-abs, GlyR-abs, LGI1-abs, or CASPR2-abs. These findings suggest that cerebrospinal fluid NSA-abs analysis should be included in the diagnostic workup of patients with rapidly progressive central nervous system syndromes, particularly when they do not fulfill the diagnostic criteria of probable or possible CJD.

Red-backed vole brain promotes highly efficient in vitro amplification of abnormal prion protein from macaque and human brains infected with variant Creutzfeldt-Jakob disease agent.

USGS Publications Warehouse

Nemecek, Julie; Nag, Nabanita; Carlson, Christina M.; Schneider, Jay R.; Heisey, Dennis M.; Johnson, Christopher J.; Asher, David M.; Gregori, Luisa

2013-01-01

Rapid antemortem tests to detect individuals with transmissible spongiform encephalopathies (TSE) would contribute to public health. We investigated a technique known as protein misfolding cyclic amplification (PMCA) to amplify abnormal prion protein (PrPTSE) from highly diluted variant Creutzfeldt-Jakob disease (vCJD)-infected human and macaque brain homogenates, seeking to improve the rapid detection of PrPTSE in tissues and blood. Macaque vCJD PrPTSE did not amplify using normal macaque brain homogenate as substrate (intraspecies PMCA). Next, we tested interspecies PMCA with normal brain homogenate of the southern red-backed vole (RBV), a close relative of the bank vole, seeded with macaque vCJD PrPTSE. The RBV has a natural polymorphism at residue 170 of the PrP-encoding gene (N/N, S/S, and S/N). We investigated the effect of this polymorphism on amplification of human and macaque vCJD PrPTSE. Meadow vole brain (170N/N PrP genotype) was also included in the panel of substrates tested. Both humans and macaques have the same 170S/S PrP genotype. Macaque PrPTSE was best amplified with RBV 170S/S brain, although 170N/N and 170S/N were also competent substrates, while meadow vole brain was a poor substrate. In contrast, human PrPTSE demonstrated a striking narrow selectivity for PMCA substrate and was successfully amplified only with RBV 170S/S brain. These observations suggest that macaque PrPTSE was more permissive than human PrPTSE in selecting the competent RBV substrate. RBV 170S/S brain was used to assess the sensitivity of PMCA with PrPTSE from brains of humans and macaques with vCJD. PrPTSE signals were reproducibly detected by Western blot in dilutions through 10-12 of vCJD-infected 10% brain homogenates. This is the first report showing PrPTSE from vCJD-infected human and macaque brains efficiently amplified with RBV brain as the substrate. Based on our estimates, PMCA showed a sensitivity that might be sufficient to detect PrPTSE in vCJD-infected human and macaque blood.

Rapidly Progressive Dementia

PubMed Central

Geschwind, Michael D.

2016-01-01

Purpose of Review: This article presents a practical and informative approach to the evaluation of a patient with a rapidly progressive dementia (RPD). Recent Findings: Prion diseases are the prototypical causes of RPD, but reversible causes of RPD might mimic prion disease and should always be considered in a differential diagnosis. Aside from prion diseases, the most common causes of RPD are atypical presentations of other neurodegenerative disorders, curable disorders including autoimmune encephalopathies, as well as some infections, and neoplasms. Numerous recent case reports suggest dural arterial venous fistulas sometimes cause RPDs. Summary: RPDs, in which patients typically develop dementia over weeks to months, require an alternative differential than the slowly progressive dementias that occur over a few years. Because of their rapid decline, patients with RPDs necessitate urgent evaluation and often require an extensive workup, typically with multiple tests being sent or performed concurrently. Jakob-Creutzfeldt disease, perhaps the prototypical RPD, is often the first diagnosis many neurologists consider when treating a patient with rapid cognitive decline. Many conditions other than prion disease, however, including numerous reversible or curable conditions, can present as an RPD. This chapter discusses some of the major etiologies for RPDs and offers an algorithm for diagnosis. PMID:27042906

Disease associated prion protein may deposit in the peripheral nervous system in human transmissible spongiform encephalopathies.

PubMed

Hainfellner, J A; Budka, H

1999-11-01

There is increasing evidence indicating involvement of the peripheral nervous system (PNS) in the pathogenesis of transmissible spongiform encephalopathies (TSEs). Immunocytochemically detectable deposits of TSE-specific abnormal prion protein (PrP(sc)) are considered as a surrogate marker for infectivity. We used anti-PrP immunocytochemistry to trace PrP(sc) deposition in spinal and enteric ganglia, and peripheral nerve in Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), and fatal familial insomnia. Discrete PrP(sc) deposits were detectable only in a few posterior root nerve fibers in an adaxonal location in one of nine CJD and the one GSS patients examined. Follicular dendritic cells of the gut and enteric nervous system were not labeled. Thus, PrP(sc) may spread to the PNS in different forms of human prion disease. In contrast to our observations in experimental scrapie (Groschup et al., Acta Neuropathol, this issue), the deposits were scant. Possible explanations for this discrepancy comprise strain difference, or centripetal (experimental scrapie) versus centrifugal (sporadic and genetic human prion diseases) spread of PrP(sc), resulting in different patterns and amounts of PrP(sc) accumulation in the PNS.

Prions and prion diseases: fundamentals and mechanistic details.

PubMed

Ryou, Chongsuk

2007-07-01

Prion diseases, often called transmissible spongiform encephalopathies (TSEs), are infectious diseases that accompany neurological dysfunctions in many mammalian hosts. Prion diseases include Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE, "mad cow disease") in cattle, scrapie in sheep, and chronic wasting disease (CWD) in deer and elks. The cause of these fatal diseases is a proteinaceous pathogen termed prion that lacks functional nucleic acids. As demonstrated in the BSE outbreak and its transmission to humans, the onset of disease is not limited to a certain species but can be transmissible from one host species to another. Such a striking nature ofprions has generated huge concerns in public health and attracted serious attention in the scientific communities. To date, the potential transmission ofprions to humans via foodbome infectiorn and iatrogenic routes has not been alleviated. Rather, the possible transmission of human to human or cervids to human aggravates the terrifying situation across the globe. In this review, basic features about prion diseases including clinical and pathological characteristics, etiology, and transmission of diseases are described. Based on recently accumulated evidences, the molecular and biochemical aspects of prions, with an emphasis on the molecular interactions involved in prion conversion that is critical during prion replication and pathogenesis, are also addressed.

Progress and problems in the biology, diagnostics, and therapeutics of prion diseases

PubMed Central

Aguzzi, Adriano; Heikenwalder, Mathias; Miele, Gino

2004-01-01

The term “prion” was introduced by Stanley Prusiner in 1982 to describe the atypical infectious agent that causes transmissible spongiform encephalopathies, a group of infectious neurodegenerative diseases that include scrapie in sheep, Creutzfeldt-Jakob disease in humans, chronic wasting disease in cervids, and bovine spongiform encephalopathy in cattle. Over the past twenty years, the word “prion” has been taken to signify various subtly different concepts. In this article, we refer to the prion as the transmissible principle underlying prion diseases, without necessarily implying any specific biochemical or structural identity. When Prusiner started his seminal work, the study of transmissible spongiform encephalopathies was undertaken by only a handful of scientists. Since that time, the “mad cow” crisis has put prion diseases on the agenda of both politicians and the media. Significant progress has been made in prion disease research, and many aspects of prion pathogenesis are now understood. And yet the diagnostic procedures available for prion diseases are not nearly as sensitive as they ought to be, and no therapeutic intervention has been shown to reliably affect the course of the diseases. This article reviews recent progress in the areas of pathogenesis of, diagnostics of, and therapy for prion diseases and highlights some conspicuous problems that remain to be addressed in each of these fields. PMID:15254579

Gene knockout of tau expression does not contribute to the pathogenesis of prion disease.

PubMed

Lawson, Victoria A; Klemm, Helen M; Welton, Jeremy M; Masters, Colin L; Crouch, Peter; Cappai, Roberto; Ciccotosto, Giuseppe D

2011-11-01

Prion diseases or transmissible spongiform encephalopathies are a group of fatal and transmissible disorders affecting the central nervous system of humans and animals. The principal agent of prion disease transmission and pathogenesis is proposed to be an abnormal protease-resistant isoform of the normal cellular prion protein. The microtubule-associated protein tau is elevated in patients with Creutzfeldt-Jakob disease. To determine whether tau expression contributes to prion disease pathogenesis, tau knockout and control wild-type mice were infected with the M1000 strain of mouse-adapted human prions. Immunohistochemical analysis for total tau expression in prion-infected wild-type mice indicated tau aggregation in the cytoplasm of a subpopulation of neurons in regions associated with spongiform change. Western immunoblot analysis of brain homogenates revealed a decrease in total tau immunoreactivity and epitope-specific changes in tau phosphorylation. No significant difference in incubation period or other disease features were observed between tau knockout and wild-type mice with clinical prion disease. These results demonstrate that, in this model of prion disease, tau does not contribute to the pathogenesis of prion disease and that changes in the tau protein profile observed in mice with clinical prion disease occurs as a consequence of the prion-induced pathogenesis.

[Variant Creutzfeldt-Jakob disease in France: estimating the number of cases related to travel to the United Kingdom between 1980 and 1995].

PubMed

Chadeau-Hyam, M; Alpérovitch, A

2005-02-01

The outbreak of variant Creutzfeldt-Jakob disease (vCJD) cases rose serious concerns about secondary transmission of the disease, particularly through blood transfusion. Protective measures leading to the exclusion of potentially infectious blood donors were settled: in France, donors who had stayed more than one year in the UK were excluded. In this work, which was part of a larger study aiming to estimate the French epidemic of vCJD, the number of vCJD cases who were infected during a trip to the UK was estimated. Those estimates may notably enable the assessment of such exclusion measures. The particular age-related structure in vCJD cases is taken into account in our simulations considering birth cohorts in the population. The total French exposure is simulated assuming the main source of infection to be dietary through consumption of mechanically recovered meat (MRM) manufactured from British bovine carcasses. Then, using a "back calculation" algorithm, all infected individuals required to produce a consistent epidemic (6 vCJD cases in 2003) was simulated. This study was exclusively focused on the part of the exposure linked to trips (beef MRM consumed in the UK while traveling) and on cases resulting from this exposure. The influence of exposure linked to trips to the UK was greater in the youngest cohort (6.3% of the total exposure) while it only accounted for 3.3% and 1% in the 1939-69 and in the pre-1939 birth cohorts respectively. Overall, exposure resulting from trips in the UK can be neglected with regards to the exposure linked to the consumption of MRM produced in France from British bovine carcasses. Consequently, French vCJD cases that would have been infected in the UK are very unlikely to occur (median: 0 case, IC 95%: (0-2)). Nevertheless, if such cases occur, they would probably occur in subjects born after 1969 and their onset would take place before 2010. Thus, unlike the situation in BSE-free countries, the causal relationship between travel in the UK and occurrence of vCJD cases cannot be underlined in France, as trips only account for a small part of the French exposure. Since trips in the UK slightly contribute to the overall French exposure, excluding people who travelled in the UK from blood donation would not influence the risk of secondary transmission.

Fatal degenerative neurologic illnesses in men who participated in wild game feasts--Wisconsin, 2002.

PubMed

2003-02-21

Creutzfeldt-Jakob disease (CJD) is a fatal neurologic disorder in humans. CJD is one of a group of conditions known as transmissible spongiform encephalopathies (TSEs), or prion diseases, that are believed to be caused by abnormally configured, host-encoded prion proteins that accumulate in the central nervous tissue. CJD has an annual incidence of approximately 1 case per million population in the United States and occurs in three forms: sporadic, genetically determined, and acquired by infection. In the latter form, the incubation period is measured typically in years. Recent evidence that prion infection can cross the species barrier between humans and cattle has raised increasing public health concerns about the possible transmission to humans of a TSE among deer and elk known as chronic wasting disease (CWD). During 1993-1999, three men who participated in wild game feasts in northern Wisconsin died of degenerative neurologic illnesses. This report documents the investigation of these deaths, which was initiated in August 2002 and which confirmed the death of only one person from CJD. Although no association between CWD and CJD was found, continued surveillance of both diseases remains important to assess the possible risk for CWD transmission to humans.

The impact of social amplification and attenuation of risk and the public reaction to mad cow disease in Canada.

PubMed

Lewis, Roxanne E; Tyshenko, Michael G

2009-05-01

Following the detection of bovine spongiform encephalopathy (BSE) in Canada, and subsequently in the United States, confidence in the safety of beef products remained high. Consumers actually increased their consumption of beef slightly after the news of an increased risk from mad cow disease, which has been interpreted as public support for beef farmers and confidence in government regulators. The Canadian public showed a markedly different reaction to the news of domestic BSE than the furious and panicked responses observed in the United Kingdom, Germany, and Japan. Using the social amplification of risk framework, we show that, while other countries displayed social amplification of risk, Canada experienced a social attenuation of risk. The attenuated reaction in Canada toward mad cow disease and increased human health risks from variant Creutzfeldt-Jakob disease (vCJD) was due to the social context at the time when BSE was discovered domestically. Mortality, morbidity, and psychosocial impacts resulting from other major events such as severe acute respiratory syndrome (SARS), West Nile virus (WNV), and the U.S.-Iraq war made the theoretical risks of BSE and vCJD a lower priority, reducing its concern as a risk issue.

Genetic epidemiology of single gene defects in Chile.

PubMed Central

Cruz-Coke, R; Moreno, R S

1994-01-01

We have studied the correlation between the ethnic structure and the prevalence of single gene defects in Chile. At present the Chilean population is approximately 64% white and 35% Amerindian with traces of other admixture. Fewer than 4% of the Chilean population are foreign born. Investigations indicate that all severe diseases and many others without impaired reproduction have mutation rates within the range of the white population. Classical ethnic diseases are very rare. Autosomal recessive disorders have a wide range of variability: cystic fibrosis has a low incidence and PKU has a similar incidence to English rates. Only 30% of the inborn errors of metabolism have been described in Chilean medical publications. In addition, no Chilean haemoglobin or haptoglobin variants have been described. Some rare inherited diseases in Chilean human isolates have been described, including achromatopsia, chondrocalcinosis, and Creutzfeldt-Jakob disease. The prevalence of intrahepatic cholestasis of pregnancy and supernumerary nipples is the highest in the world and they are associated with aboriginal origin. Single gene defects in Chile are probably shaped by factors related to its ethnic population structure. These local rare single gene defects may be good markers of population admixture for genetic epidemiological studies. PMID:7815439

Octarepeat region flexibility impacts prion function, endoproteolysis and disease manifestation

PubMed Central

Lau, Agnes; McDonald, Alex; Daude, Nathalie; Mays, Charles E; Walter, Eric D; Aglietti, Robin; Mercer, Robert CC; Wohlgemuth, Serene; van der Merwe, Jacques; Yang, Jing; Gapeshina, Hristina; Kim, Chae; Grams, Jennifer; Shi, Beipei; Wille, Holger; Balachandran, Aru; Schmitt-Ulms, Gerold; Safar, Jiri G; Millhauser, Glenn L; Westaway, David

2015-01-01

The cellular prion protein (PrPC) comprises a natively unstructured N-terminal domain, including a metal-binding octarepeat region (OR) and a linker, followed by a C-terminal domain that misfolds to form PrPSc in Creutzfeldt-Jakob disease. PrPC β-endoproteolysis to the C2 fragment allows PrPSc formation, while α-endoproteolysis blocks production. To examine the OR, we used structure-directed design to make novel alleles, ‘S1’ and ‘S3’, locking this region in extended or compact conformations, respectively. S1 and S3 PrP resembled WT PrP in supporting peripheral nerve myelination. Prion-infected S1 and S3 transgenic mice both accumulated similar low levels of PrPSc and infectious prion particles, but differed in their clinical presentation. Unexpectedly, S3 PrP overproduced C2 fragment in the brain by a mechanism distinct from metal-catalysed hydrolysis reported previously. OR flexibility is concluded to impact diverse biological endpoints; it is a salient variable in infectious disease paradigms and modulates how the levels of PrPSc and infectivity can either uncouple or engage to drive the onset of clinical disease. PMID:25661904

[Eyelid retraction of neurologic origin: Report of three cases].

PubMed

Cartier R, Luis; Guzmán S, Jorge; Pasquali F, Renzo

2017-02-01

Eyelid retraction, has received limited attention and it has passively been interpreted as the result of an overactive levator palpebrae superioris muscle secondary to midbrain injury. However, eyelid retractions can occur in other neurological diseases, not directly related with the midbrain. We report three patients who developed eyelid retraction. One patient had a bilateral eyelid retraction, related with Creutzfeldt-Jakob disease (CJD). Another patient had a unilateral right eyelid retraction associated with a thalamic-mesencephalic infarct. The third patient had a bilateral pontine infarction on magnetic resonance imaging. In the patient with CJD, eyelid retraction did not subside. Among patients with infarctions, the retraction persisted after focal symptoms had subsided, showing an evolution that was apparently independent of the basic process. The analysis of these patients allows us to conclude that the pathogenesis of eyelid retraction includes supranuclear mechanisms in both the development and maintenance of the phenomenon. Unilateral or bilateral eyelid retraction does not alter the normal function of eyelid, which ever had normal close eye blink. In these reported cases, a hyperactivity of levator palpebrae superioris muscle was clinically ruled out.

[VGKC-complex antibodies].

PubMed

Watanabe, Osamu

2013-04-01

Various antibodies are associated with voltage-gated potassium channels (VGKCs). Representative antibodies to VGKCs were first identified by radioimmunoassays using radioisotope-labeled alpha-dendrotoxin-VGKCs solubilized from rabbit brain. These antibodies were detected only in a proportion of patients with acquired neuromyotonia (Isaacs' syndrome). VGKC antibodies were also detected in patients with Morvan's syndrome and in those with a form of autoimmune limbic encephalitis. Recent studies indicated that the "VGKC" antibodies are mainly directed toward associated proteins (for example LGI-1 and CASPR-2) that complex with the VGKCs themselves. The "VGKC" antibodies are now commonly known as VGKC-complex antibodies. In general, LGI-1 antibodies are most commonly detected in patients with limbic encephalitis with syndrome of inappropriate secretion of antidiuretic hormone. CASPR-2 antibodies are present in the majority of patients with Morvan's syndrome. These patients develop combinations of CNS symptoms, autonomic dysfunction, and peripheral nerve hyperexcitability. Furthermore, VGKC-complex antibodies are tightly associated with chronic idiopathic pain. Hyperexcitability of nociceptive pathways has also been implicated. These antibodies may be detected in sera of some patients with neurodegenerative diseases (for example, amyotrophic lateral sclerosis and Creutzfeldt-Jakob disease).

Prion disease tempo determined by host-dependent substrate reduction

PubMed Central

Mays, Charles E.; Kim, Chae; Haldiman, Tracy; van der Merwe, Jacques; Lau, Agnes; Yang, Jing; Grams, Jennifer; Di Bari, Michele A.; Nonno, Romolo; Telling, Glenn C.; Kong, Qingzhong; Langeveld, Jan; McKenzie, Debbie; Westaway, David; Safar, Jiri G.

2014-01-01

The symptoms of prion infection can take years or decades to manifest following the initial exposure. Molecular markers of prion disease include accumulation of the misfolded prion protein (PrPSc), which is derived from its cellular precursor (PrPC), as well as downregulation of the PrP-like Shadoo (Sho) glycoprotein. Given the overlapping cellular environments for PrPC and Sho, we inferred that PrPC levels might also be altered as part of a host response during prion infection. Using rodent models, we found that, in addition to changes in PrPC glycosylation and proteolytic processing, net reductions in PrPC occur in a wide range of prion diseases, including sheep scrapie, human Creutzfeldt-Jakob disease, and cervid chronic wasting disease. The reduction in PrPC results in decreased prion replication, as measured by the protein misfolding cyclic amplification technique for generating PrPSc in vitro. While PrPC downregulation is not discernible in animals with unusually short incubation periods and high PrPC expression, slowly evolving prion infections exhibit downregulation of the PrPC substrate required for new PrPSc synthesis and as a receptor for pathogenic signaling. Our data reveal PrPC downregulation as a previously unappreciated element of disease pathogenesis that defines the extensive, presymptomatic period for many prion strains. PMID:24430187

Rapid Typing of Transmissible Spongiform Encephalopathy Strains with Differential ELISA

PubMed Central

Simon, Stéphanie; Nugier, Jérôme; Morel, Nathalie; Boutal, Hervé; Créminon, Christophe; Benestad, Sylvie L.; Andréoletti, Olivier; Lantier, Frédéric; Bilheude, Jean-Marc; Feyssaguet, Muriel; Biacabe, Anne-Gaëlle; Baron, Thierry

2008-01-01

The bovine spongiform encephalopathy (BSE) agent has been transmitted to humans, leading to variant Creutzfeldt-Jakob disease. Sheep and goats can be experimentally infected by BSE and have been potentially exposed to natural BSE; however, whether BSE can be transmitted to small ruminants is not known. Based on the particular biochemical properties of the abnormal prion protein (PrPsc) associated with BSE, and particularly the increased degradation induced by proteinase K in the N terminal part of PrPsc, we have developed a rapid ELISA designed to distinguish BSE from other scrapie strains. This assay clearly discriminates experimental ovine BSE from other scrapie strains and was used to screen 260 transmissible spongiform encephalopathy (TSE)–infected small ruminant samples identified by the French active surveillance network (2002/2003). In this context, this test has helped to identify the first case of natural BSE in a goat and can be used to classify TSE isolates based on the proteinase K sensitivity of PrPsc. PMID:18394279

Spontaneous generation of rapidly transmissible prions in transgenic mice expressing wild-type bank vole prion protein.

PubMed

Watts, Joel C; Giles, Kurt; Stöhr, Jan; Oehler, Abby; Bhardwaj, Sumita; Grillo, Sunny K; Patel, Smita; DeArmond, Stephen J; Prusiner, Stanley B

2012-02-28

Currently, there are no animal models of the most common human prion disorder, sporadic Creutzfeldt-Jakob disease (CJD), in which prions are formed spontaneously from wild-type (WT) prion protein (PrP). Interestingly, bank voles (BV) exhibit an unprecedented promiscuity for diverse prion isolates, arguing that bank vole PrP (BVPrP) may be inherently prone to adopting misfolded conformations. Therefore, we constructed transgenic (Tg) mice expressing WT BVPrP. Tg(BVPrP) mice developed spontaneous CNS dysfunction between 108 and 340 d of age and recapitulated the hallmarks of prion disease, including spongiform degeneration, pronounced astrogliosis, and deposition of alternatively folded PrP in the brain. Brain homogenates of ill Tg(BVPrP) mice transmitted disease to Tg(BVPrP) mice in ∼35 d, to Tg mice overexpressing mouse PrP in under 100 d, and to WT mice in ∼185 d. Our studies demonstrate experimentally that WT PrP can spontaneously form infectious prions in vivo. Thus, Tg(BVPrP) mice may be useful for studying the spontaneous formation of prions, and thus may provide insight into the etiology of sporadic CJD.

Amyloid Structure and Assembly: Insights from Scanning Transmission Electron Microscopy

PubMed Central

Goldsbury, Claire; Baxa, Ulrich; Simon, Martha N.; Steven, Alasdair C.; Engel, Andreas; Wall, Joseph S.; Aebi, Ueli; Müller, Shirley A.

2010-01-01

Amyloid fibrils are filamentous protein aggregates implicated in several common diseases like Alzheimer’s disease and type II diabetes. Similar structures are also the molecular principle of the infectious spongiform encephalopathies like Creutzfeldt-Jakob disease in humans, scrapie in sheep, and of the so-called yeast prions, inherited non-chromosomal elements found in yeast and fungi. Scanning transmission electron microscopy (STEM) is often used to delineate the assembly mechanism and structural properties of amyloid aggregates. In this review we consider specifically contributions and limitations of STEM for the investigation of amyloid assembly pathways, fibril polymorphisms and structural models of amyloid fibrils. This type of microscopy provides the only method to directly measure the mass-per-length (MPL) of individual filaments. Made on both in vitro assembled and ex vivo samples, STEM mass measurements have illuminated the hierarchical relationships between amyloid fibrils and revealed that polymorphic fibrils and various globular oligomers can assemble simultaneously from a single polypeptide. The MPLs also impose strong constraints on possible packing schemes, assisting in molecular model building when combined with high-resolution methods like solid-state nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR). PMID:20868754

A vital fluid: risk, controversy and the politics of blood donation in the era of "mad cow disease".

PubMed

O'Neill, Kate

2003-10-01

This article examines the reasons for, and likely impact of, the decision by the US and other countries to permanently defer blood donors who have spent time in Britain or Europe, for fear they may transmit new variant Creutzfeldt-Jakob disease (vCJD), the human form of "mad cow disease". It begins by discussing how vCJD and blood transfusion are linked, and how these have been translated into policy. First, maintaining a safe and stable supply of blood entails not only maintaining the trust of recipients in the system, but also that of donors, who need to be assured that their blood will be welcomed and used. Often, the balance, once upset, is regained by sacrificing donors, but accompanying costs might also be high. Second, the article highlights the impact of various forms of globalization -of commerce, disease and travel, and immigration- on blood policies and public and policy attitudes. Third, it assesses the decision by the US to restrict blood donations from Europeans and travelers to combat such a pervasive risk. The conclusion discusses how donor deferral policies may be interpreted by the public in the light of earlier discussions, and raises issues for future research.

Soluble Aβ aggregates can inhibit prion propagation.

PubMed

Sarell, Claire J; Quarterman, Emma; Yip, Daniel C-M; Terry, Cassandra; Nicoll, Andrew J; Wadsworth, Jonathan D F; Farrow, Mark A; Walsh, Dominic M; Collinge, John

2017-11-01

Mammalian prions cause lethal neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) and consist of multi-chain assemblies of misfolded cellular prion protein (PrP C ). Ligands that bind to PrP C can inhibit prion propagation and neurotoxicity. Extensive prior work established that certain soluble assemblies of the Alzheimer's disease (AD)-associated amyloid β-protein (Aβ) can tightly bind to PrP C , and that this interaction may be relevant to their toxicity in AD. Here, we investigated whether such soluble Aβ assemblies might, conversely, have an inhibitory effect on prion propagation. Using cellular models of prion infection and propagation and distinct Aβ preparations, we found that the form of Aβ assemblies which most avidly bound to PrP in vitro also inhibited prion infection and propagation. By contrast, forms of Aβ which exhibit little or no binding to PrP were unable to attenuate prion propagation. These data suggest that soluble aggregates of Aβ can compete with prions for binding to PrP C and emphasize the bidirectional nature of the interplay between Aβ and PrP C in Alzheimer's and prion diseases. Such inhibitory effects of Aβ on prion propagation may contribute to the apparent fall-off in the incidence of sporadic CJD at advanced age where cerebral Aβ deposition is common. © 2017 The Authors.

Polymorphism at 129 dictates metastable conformations of the human prion protein N-terminal β-sheet† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c6sc03275c Click here for additional data file.

PubMed Central

Paz, S. Alexis; Vanden-Eijnden, Eric

2017-01-01

We study the thermodynamic stability of the native state of the human prion protein using a new free-energy method, replica-exchange on-the-fly parameterization. This method is designed to overcome hidden-variable sampling limitations to yield nearly error-free free-energy profiles along a conformational coordinate. We confirm that all four (M129V, D178N) polymorphs have a ground-state conformation with three intact β-sheet hydrogen bonds. Additionally, they are observed to have distinct metastabilities determined by the side-chain at position 129. We rationalize these findings with reference to the prion “strain” hypothesis, which links the variety of transmissible spongiform encephalopathy phenotypes to conformationally distinct infectious prion forms and classifies distinct phenotypes of sporadic Creutzfeldt-Jakob disease based solely on the 129 polymorphism. Because such metastable structures are not easily observed in structural experiments, our approach could potentially provide new insights into the conformational origins of prion diseases and other pathologies arising from protein misfolding and aggregation. PMID:28451263

Impact of vCJD on blood supply.

PubMed

Seitz, Rainer; von Auer, Friedger; Blümel, Johannes; Burger, Reinhard; Buschmann, Anne; Dietz, Klaus; Heiden, Margarethe; Hitzler, Walter E; Klamm, Horst; Kreil, Thomas; Kretzschmar, Hans; Nübling, Micha; Offergeld, Ruth; Pauli, Georg; Schottstedt, Volkmar; Volkers, Peter; Zerr, Inga

2007-04-01

Variant Creutzfeldt-Jakob disease (vCJD) is an at present inevitably lethal neurodegenerative disease which can only be diagnosed definitely post mortem. The majority of the approximately 200 victims to date have resided in the UK where most contaminated beef materials entered the food chain. Three cases in the UK demonstrated that vCJD can be transmitted by blood transfusion. Since BSE and vCJD have spread to several countries outside the UK, it appears advisable that specific risk assessments be carried out in different countries and geographic areas. This review explains the approach adopted by Germany in assessing the risk and considering precautionary measures. A fundamental premise is that the feeding chain of cattle and the food chain have been successfully and permanently cleared from contaminated material. This raises the question of whether transmissions via blood transfusions could have the potential to perpetuate vCJD in mankind. A model calculation based on actual population data showed, however, that this would not be the case. Moreover, an exclusion of transfusion recipients from blood donation would add very little to the safety of blood transfusions, but would have a considerable impact on blood supply. Therefore, an exclusion of transfusion recipients was not recommended in Germany.

A crucial role for B cells in neuroinvasive scrapie.

PubMed

Brandner, S; Klein, M A; Aguzzi, A

1999-02-01

Although prions are most efficiently propagated via intracerebral inoculation, peripheral administration has caused kuru [Gajdusek et al, 1966], iatrogenic Creutzfeldt-Jakob disease (CJD) [Gibbs et al, 1997], bovine spongiform encephalitis (BSE), and new variant CJD [Hill et al, 1997; Bruce et al, 1997]. Neurological disease after peripheral inoculation depends on prion expansion within cells of the lymphoreticular system (LRS) [Lasmezas et al. 1996; Wilesmith et al, 1992]. In order to identify the nature of the latter cells, we inoculated a panel of immune deficient mice with prions intraperitoneally. While defects affecting only T lymphocytes had no apparent effect, all mutations affecting differentiation and responses of B lymphocytes prevented development of clinical scrapie. Since absence of B cells and of antibodies correlates with severe defects in follicular dendritic cells (FDCs), the lack of any of these three components may prevent clinical scrapie. Yet, mice expressing immunoglobulins exclusively of the M subclass without detectable specificity for PrPc, and mice with differentiated B cells but lacking functional FDCs, developed scrapie after peripheral inoculation: therefore, differentiated B cells appear to play a crucial role in neuroinvasion of scrapie regardless of B-cell receptor specificity.

SERS Detection of Amyloid Oligomers on Metallorganic-Decorated Plasmonic Beads.

PubMed

Guerrini, Luca; Arenal, Raul; Mannini, Benedetta; Chiti, Fabrizio; Pini, Roberto; Matteini, Paolo; Alvarez-Puebla, Ramon A

2015-05-13

Protein misfolded proteins are among the most toxic endogenous species of macromolecules. These chemical entities are responsible for neurodegenerative disorders such as Alzheimer's, Parkinson's, Creutzfeldt-Jakob's and different non-neurophatic amyloidosis. Notably, these oligomers show a combination of marked heterogeneity and low abundance in body fluids, which have prevented a reliable detection by immunological methods so far. Herein we exploit the selectivity of proteins to react with metallic ions and the sensitivity of surface-enhanced Raman spectroscopy (SERS) toward small electronic changes in coordination compounds to design and engineer a reliable optical sensor for protein misfolded oligomers. Our strategy relies on the functionalization of Au nanoparticle-decorated polystyrene beads with an effective metallorganic Raman chemoreceptor, composed by Al(3+) ions coordinated to 4-mercaptobenzoic acid (MBA) with high Raman cross-section, that selectively binds aberrant protein oligomers. The mechanical deformations of the MBA phenyl ring upon complexation with the oligomeric species are registered in its SERS spectrum and can be quantitatively correlated with the concentration of the target biomolecule. The SERS platform used here appears promising for future implementation of diagnostic tools of aberrant species associated with protein deposition diseases, including those with a strong social and economic impact, such as Alzheimer's and Parkinson's diseases.

The price of the precautionary principle: cost-effectiveness of BSE intervention strategies in The Netherlands.

PubMed

Benedictus, A; Hogeveen, H; Berends, B R

2009-06-01

Since 1996, bovine spongiform encephalopathy (BSE) in cattle has been linked to a new variant of Creutzfeldt-Jakob disease (vCJD), a fatal brain disease in man. This paper assessed the cost-effectiveness of BSE control strategies instituted by the European Commission. In a Monte Carlo simulation model, a non-intervention baseline scenario was compared to three intervention strategies: removal of specified risk materials from slaughter animals, post-mortem testing for BSE and the culling of feed and age cohorts of BSE cases. The food risk in the baseline scenario ranged from 16.98 lost life years in 2002 to 2.69 lost life years in 2005. Removing specified risk materials removal practices, post-mortem testing and post-mortem testing plus cohort culling reduced this risk with 93%, 82.7% and 83.1%. The estimated cost-effectiveness of all BSE measures in The Netherlands ranged from 4.3 million euros per life year saved in 2002 to 17.7 million euros in 2005. It was discussed that the cost-effectiveness of BSE control strategies will further deviate from regular health economics thresholds as BSE prevalence and incidence declines.

Nanomechanical properties of single amyloid fibrils

NASA Astrophysics Data System (ADS)

Sweers, K. K. M.; Bennink, M. L.; Subramaniam, V.

2012-06-01

Amyloid fibrils are traditionally associated with neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease or Creutzfeldt-Jakob disease. However, the ability to form amyloid fibrils appears to be a more generic property of proteins. While disease-related, or pathological, amyloid fibrils are relevant for understanding the pathology and course of the disease, functional amyloids are involved, for example, in the exceptionally strong adhesive properties of natural adhesives. Amyloid fibrils are thus becoming increasingly interesting as versatile nanobiomaterials for applications in biotechnology. In the last decade a number of studies have reported on the intriguing mechanical characteristics of amyloid fibrils. In most of these studies atomic force microscopy (AFM) and atomic force spectroscopy play a central role. AFM techniques make it possible to probe, at nanometer length scales, and with exquisite control over the applied forces, biological samples in different environmental conditions. In this review we describe the different AFM techniques used for probing mechanical properties of single amyloid fibrils on the nanoscale. An overview is given of the existing mechanical studies on amyloid. We discuss the difficulties encountered with respect to the small fibril sizes and polymorphic behavior of amyloid fibrils. In particular, the different conformational packing of monomers within the fibrils leads to a heterogeneity in mechanical properties. We conclude with a brief outlook on how our knowledge of these mechanical properties of the amyloid fibrils can be exploited in the construction of nanomaterials from amyloid fibrils.

Prion infectivity in the spleen of a PRNP heterozygous individual with subclinical variant Creutzfeldt–Jakob disease

PubMed Central

Bishop, Matthew T.; Diack, Abigail B.; Ritchie, Diane L.; Ironside, James W.; Will, Robert G.

2013-01-01

Blood transfusion has been identified as a source of human-to-human transmission of variant Creutzfeldt–Jakob disease. Three cases of variant Creutzfeldt–Jakob disease have been identified following red cell transfusions from donors who subsequently developed variant Creutzfeldt–Jakob disease and an asymptomatic red cell transfusion recipient, who did not die of variant Creutzfeldt–Jakob disease, has been identified with prion protein deposition in the spleen and a lymph node, but not the brain. This individual was heterozygous (MV) at codon 129 of the prion protein gene (PRNP), whereas all previous definite and probable cases of variant Creutzfeldt–Jakob disease have been methionine homozygotes (MM). A critical question for public health is whether the prion protein deposition reported in peripheral tissues from this MV individual correlates with infectivity. Additionally it is important to establish whether the PRNP codon 129 genotype has influenced the transmission characteristics of the infectious agent. Brain and spleen from the MV blood recipient were inoculated into murine strains that have consistently demonstrated transmission of the variant Creutzfeldt–Jakob disease agent. Mice were assessed for clinical and pathological signs of disease and transmission data were compared with other transmission studies in variant Creutzfeldt–Jakob disease, including those on the spleen and brain of the donor to the index case. Transmission of variant Creutzfeldt–Jakob disease was observed from the MV blood recipient spleen, but not from the brain, whereas there was transmission from both spleen and brain tissues from the red blood cell donor. Longer incubation times were observed for the blood donor spleen inoculum compared with the blood donor brain inoculum, suggesting lower titres of infectivity in the spleen. The distribution of vacuolar pathology and abnormal prion protein in infected mice were similar following inoculation with both donor and recipient spleen homogenates, providing initial evidence of similar transmission properties after propagation in PRNP codon 129 MV and MM individuals. These studies demonstrate that spleen tissue from a PRNP MV genotype individual can propagate the variant Creutzfeldt–Jakob disease agent and that the infectious agent can be present in the spleen without CNS involvement. PMID:23449776

BSE Case Associated with Prion Protein Gene Mutation

PubMed Central

Richt, Jürgen A.; Hall, S. Mark

2008-01-01

Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy (TSE) of cattle and was first detected in 1986 in the United Kingdom. It is the most likely cause of variant Creutzfeldt-Jakob disease (CJD) in humans. The origin of BSE remains an enigma. Here we report an H-type BSE case associated with the novel mutation E211K within the prion protein gene (Prnp). Sequence analysis revealed that the animal with H-type BSE was heterozygous at Prnp nucleotides 631 through 633. An identical pathogenic mutation at the homologous codon position (E200K) in the human Prnp has been described as the most common cause of genetic CJD. This finding represents the first report of a confirmed case of BSE with a potential pathogenic mutation within the bovine Prnp gene. A recent epidemiological study revealed that the K211 allele was not detected in 6062 cattle from commercial beef processing plants and 42 cattle breeds, indicating an extremely low prevalence of the E211K variant (less than 1 in 2000) in cattle. PMID:18787697

Subacute Noninfective Inflammatory Encephalopathy: Our Experience and Diagnostic Problems

PubMed Central

Chandra, Sadanandavalli Retnaswami; Viswanathan, Lakshminarayanapuram Gopal; Sindhu, Dodmalur Malikarjuna; Pai, Anupama Ramakanth

2017-01-01

Introduction: Immune dysregulation associated encephalopathies present with significant psychiatric manifestations and only a few soft neurological and general systemic features. They are generally resistant to treatment with psychiatric medications. Generalized orthostatic myoclonus and faciobrachial dystonic seizures are mistaken as Creutzfeldt-Jakob disease and subacute sclerosing panencephalitis. Patients and Methods: Forty-two patients seen during 2010–2015 and diagnosed as noninfective encephalopathy were analyzed. Those patients with infective causes and those who had significant features of systemic manifestations of vasculitis and other disorders of central nervous system were excluded from the study. They were investigated with cerebrospinal fluid imaging, electroencephalogram (EEG), and antibody profile. Results: More than 70% patients had psychiatric manifestation as presenting features and reported to psychiatrist. Three patients had paraneoplastic and others N-methyl-D-aspartate, voltage-gated potassium channel, thyroid peroxidase, antinuclear antibody related, and few were due to unknown antibody. Conclusion: Serious diagnostic errors are common and early diagnosis is based on high degree suspicion in patients presenting with new-onset refractory psychosis. Soft neurological features should be looked for and EEG serves as a very sensitive tool in establishing organicity. PMID:28515556

A New Approach for Detection Improvement of the Creutzfeldt-Jakob Disorder through a Specific Surface Chemistry Applied onto Titration Well

PubMed Central

Mille, Caroline; Debarnot, Dominique; Zorzi, Willy; Moualij, Benaissa El; Quadrio, Isabelle; Perret-Liaudet, Armand; Coudreuse, Arnaud; Legeay, Gilbert; Poncin-Epaillard, Fabienne

2012-01-01

This work illustrates the enhancement of the sensitivity of the ELISA titration for recombinant human and native prion proteins, while reducing other non-specific adsorptions that could increase the background signal and lead to a low sensitivity and false positives. It is achieved thanks to the association of plasma chemistry and coating with different amphiphilic molecules bearing either ionic charges and/or long hydrocarbon chains. The treated support by 3-butenylamine hydrochloride improves the signal detection of recombinant protein, while surface modification with the 3,7-dimethylocta-2,6-dien-1-diamine (geranylamine) enhances the sensitivity of the native protein. Beside the surface chemistry effect, these different results are associated with protein conformation. PMID:25586034

Profoundly different prion diseases in knock-in mice carrying single PrP codon substitutions associated with human diseases.

PubMed

Jackson, Walker S; Borkowski, Andrew W; Watson, Nicki E; King, Oliver D; Faas, Henryk; Jasanoff, Alan; Lindquist, Susan

2013-09-03

In man, mutations in different regions of the prion protein (PrP) are associated with infectious neurodegenerative diseases that have remarkably different clinical signs and neuropathological lesions. To explore the roots of this phenomenon, we created a knock-in mouse model carrying the mutation associated with one of these diseases [Creutzfeldt-Jakob disease (CJD)] that was exactly analogous to a previous knock-in model of a different prion disease [fatal familial insomnia (FFI)]. Together with the WT parent, this created an allelic series of three lines, each expressing the same protein with a single amino acid difference, and with all native regulatory elements intact. The previously described FFI mice develop neuronal loss and intense reactive gliosis in the thalamus, as seen in humans with FFI. In contrast, CJD mice had the hallmark features of CJD, spongiosis and proteinase K-resistant PrP aggregates, initially developing in the hippocampus and cerebellum but absent from the thalamus. A molecular transmission barrier protected the mice from any infectious prion agents that might have been present in our mouse facility and allowed us to conclude that the diseases occurred spontaneously. Importantly, both models created agents that caused a transmissible neurodegenerative disease in WT mice. We conclude that single codon differences in a single gene in an otherwise normal genome can cause remarkably different neurodegenerative diseases and are sufficient to create distinct protein-based infectious elements.

Sod1 deficiency reduces incubation time in mouse models of prion disease.

PubMed

Akhtar, Shaheen; Grizenkova, Julia; Wenborn, Adam; Hummerich, Holger; Fernandez de Marco, Mar; Brandner, Sebastian; Collinge, John; Lloyd, Sarah E

2013-01-01

Prion infections, causing neurodegenerative conditions such as Creutzfeldt-Jakob disease and kuru in humans, scrapie in sheep and BSE in cattle are characterised by prolonged and variable incubation periods that are faithfully reproduced in mouse models. Incubation time is partly determined by genetic factors including polymorphisms in the prion protein gene. Quantitative trait loci studies in mice and human genome-wide association studies have confirmed that multiple genes are involved. Candidate gene approaches have also been used and identified App, Il1-r1 and Sod1 as affecting incubation times. In this study we looked for an association between App, Il1-r1 and Sod1 representative SNPs and prion disease incubation time in the Northport heterogeneous stock of mice inoculated with the Chandler/RML prion strain. No association was seen with App, however, significant associations were seen with Il1-r1 (P = 0.02) and Sod1 (P<0.0001) suggesting that polymorphisms at these loci contribute to the natural variation observed in incubation time. Furthermore, following challenge with Chandler/RML, ME7 and MRC2 prion strains, Sod1 deficient mice showed highly significant reductions in incubation time of 20, 13 and 24%, respectively. No differences were detected in Sod1 expression or activity. Our data confirm the protective role of endogenous Sod1 in prion disease.

Tricyclic antidepressants, quinacrine and a novel, synthetic chimera thereof clear prions by destabilizing detergent-resistant membrane compartments.

PubMed

Klingenstein, Ralf; Löber, Stefan; Kujala, Pekka; Godsave, Susan; Leliveld, S Rutger; Gmeiner, Peter; Peters, Peter J; Korth, Carsten

2006-08-01

Prion diseases are invariably fatal, neurodegenerative diseases transmitted by an infectious agent, PrPSc, a pathogenic, conformational isoform of the normal prion protein (PrPC). Heterocyclic compounds such as acridine derivatives like quinacrine abolish prion infectivity in a cell culture model of prion disease. Here, we report that these compounds execute their antiprion activity by redistributing cholesterol from the plasma membrane to intracellular compartments, thereby destabilizing membrane domains. Our findings are supported by the fact that structurally unrelated compounds with known cholesterol-redistributing effects - U18666A, amiodarone, and progesterone - also possessed high antiprion potency. We show that tricyclic antidepressants (e.g. desipramine), another class of heterocyclic compounds, displayed structure-dependent antiprion effects and enhanced the antiprion effects of quinacrine, allowing lower doses of both drugs to be used in combination. Treatment of ScN2a cells with quinacrine or desipramine induced different ultrastructural and morphological changes in endosomal compartments. We synthesized a novel drug from quinacrine and desipramine, termed quinpramine, that led to a fivefold increase in antiprion activity compared to quinacrine with an EC50 of 85 nm. Furthermore, simvastatin, an inhibitor of cholesterol biosynthesis, acted synergistically with both heterocyclic compounds to clear PrPSc. Our data suggest that a cocktail of drugs targeting the lipid metabolism that controls PrP conversion may be the most efficient in treating Creutzfeldt-Jakob disease.

Molecular pathogenesis of sporadic prion diseases in man

PubMed Central

Safar, Jiri G.

2012-01-01

The yeast, fungal and mammalian prions determine heritable and infectious traits that are encoded in alternative conformations of proteins. They cause lethal sporadic, familial and infectious neurodegenerative conditions in man, including Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), kuru, sporadic fatal insomnia (SFI) and likely variable protease-sensitive prionopathy (VPSPr). The most prevalent of human prion diseases is sporadic (s)CJD. Recent advances in amplification and detection of prions led to considerable optimism that early and possibly preclinical diagnosis and therapy might become a reality. Although several drugs have already been tested in small numbers of sCJD patients, there is no clear evidence of any agent’s efficacy. Therefore, it remains crucial to determine the full spectrum of sCJD prion strains and the conformational features in the pathogenic human prion protein governing replication of sCJD prions. Research in this direction is essential for the rational development of diagnostic as well as therapeutic strategies. Moreover, there is growing recognition that fundamental processes involved in human prion propagation – intercellular induction of protein misfolding and seeded aggregation of misfolded host proteins – are of far wider significance. This insight leads to new avenues of research in the ever-widening spectrum of age-related human neurodegenerative diseases that are caused by protein misfolding and that pose a major challenge for healthcare. PMID:22421210

Application of Atomic Dielectric Resonance Spectroscopy for the screening of blood samples from patients with clinical variant and sporadic CJD

PubMed Central

Fagge, Timothy J; Barclay, G Robin; Stove, G Colin; Stove, Gordon; Robinson, Michael J; Head, Mark W; Ironside, James W; Turner, Marc L

2007-01-01

Background Sub-clinical variant Creutzfeldt-Jakob disease (vCJD) infection and reports of vCJD transmission through blood transfusion emphasise the need for blood screening assays to ensure the safety of blood and transplanted tissues. Most assays aim to detect abnormal prion protein (PrPSc), although achieving required sensitivity is a challenge. Methods We have used innovative Atomic Dielectric Resonance Spectroscopy (ADRS), which determines dielectric properties of materials which are established by reflectivity and penetration of radio/micro waves, to analyse blood samples from patients and controls to identify characteristic ADR signatures unique to blood from vCJD and to sCJD patients. Initial sets of blood samples from vCJD, sCJD, non-CJD neurological diseases and normal healthy adults (blood donors) were screened as training samples to determine group-specific ADR characteristics, and provided a basis for classification of blinded sets of samples. Results Blood sample groups from vCJD, sCJD, non-CJD neurological diseases and normal healthy adults (blood donors) screened by ADRS were classified with 100% specificity and sensitivity, discriminating these by a co-variance expert analysis system. Conclusion ADRS appears capable of recognising and discriminating serum samples from vCJD, sCJD, non-CJD neurological diseases, and normal healthy adults, and might be developed to provide a system for primary screening or confirmatory assay complementary to other screening systems. PMID:17760958

A novel PRNP Y218N mutation in Gerstmann-Sträussler-Scheinker disease with neurofibrillary degeneration.

PubMed

Alzualde, Ainhoa; Indakoetxea, Begoña; Ferrer, Isidre; Moreno, Fermin; Barandiaran, Myriam; Gorostidi, Ana; Estanga, Ainara; Ruiz, Irune; Calero, Miguel; van Leeuwen, Fred W; Atares, Begoña; Juste, Ramón; Rodriguez-Martínez, Ana Belén; López de Munain, Adolfo

2010-08-01

Gerstmann-Sträussler-Scheinker (GSS) disease is a prion disease associated with prion protein gene (PRNP) mutations. We report a novel PRNP mutation (Y218N) associated with GSS disease in a pathologically confirmed case and in two other affected family members. The clinical features of these cases met criteria for possible Alzheimer disease and possible frontotemporal dementia. Neuropathologic analysis revealed deposition of proteinase K-resistant prion protein (PrP(res)), widespread hyperphosphorylated tau pathology, abnormal accumulation of mitochondria in the vicinity of PrP deposits, and expression of mutant ubiquitin (UBB(+1)) in neurofibrillary tangles and dystrophic neurites. Prion protein immunoblotting using 3F4 and 1E4 antibodies disclosed multiple bands ranging from approximately 20 kd to 80 kd and lower bands of 15 kd and approximately 10 kd, the latter only seen after a long incubation. These bands were partially resistant to proteinase K pretreatment. This pattern differs from those seen in Creutzfeldt-Jakob disease andresembles those reported in other GSS cases. The approximately 10kd band was recognized with anti-PrP C-terminus antibodies but not with anti-N terminus antibodies, suggesting PrP truncation at the N terminal. This new mutation extends the list of known mutations responsible for GSS disease and reinforces its clinical heterogeneity. Genetic examination of the PRNP gene should be included in the workup of patients with poorly classifiable dementia.

Proteinase-activated receptor 2 and disease biomarkers in cerebrospinal fluid in cases with autopsy-confirmed prion diseases and other neurodegenerative diseases.

PubMed

Rohan, Zdenek; Smetakova, Magdalena; Kukal, Jaromir; Rusina, Robert; Matej, Radoslav

2015-03-31

Proteinase-activated receptor 2 (PAR-2) has been shown to promote both neurotoxic and neuroprotective effects. Similarly, other routinely used nonspecific markers of neuronal damage can be found in cerebrospinal fluid (CSF) and can be used as biomarkers for different neurodegenerative disorders. Using enzyme-linked immunosorbent assays and western blotting we assessed PAR-2, total-tau, phospho-tau, beta-amyloid levels, and protein 14-3-3 in the CSF of former patients who had undergone a neuropathological autopsy after death and who had been definitively diagnosed with a prion or other neurodegenerative disease. We did not find any significant correlation between levels of PAR-2 and other biomarkers, nor did we find any differences in PAR-2 levels between prion diseases and other neurodegenerative conditions. However, we confirmed that very high total-tau levels were significantly associated with definitive prion diagnoses and exhibited greater sensitivity and specificity than protein 14-3-3, which is routinely used as a marker. Our study showed that PAR-2, in CSF, was not specifically altered in prion diseases compared to other neurodegenerative conditions. Our results also confirmed that very high total-tau protein CSF levels were significantly associated with a definitive Creutzfeldt-Jakob disease (CJD) diagnosis and should be routinely tested as a diagnostic marker. Observed individual variability in CSF biomarkers provide invaluable feedback from neuropathological examinations even in "clinically certain" cases.

Observance of Sterilization Protocol Guideline Procedures of Critical Instruments for Preventing Iatrogenic Transmission of Creutzfeldt-Jakob Disease in Dental Practice in France, 2017

PubMed Central

Bourgeois, Denis; Dussart, Claude; Saliasi, Ina; Laforest, Laurent; Tramini, Paul; Carrouel, Florence

2018-01-01

Effective sterilization of reusable instruments contaminated by Creutzfeldt–Jakob disease in dental care is a crucial issue for public health. The present cross-sectional study investigated how the recommended procedures for sterilization were implemented by French dental practices in real-world settings. A sample of dental practices was selected in the French Rhône-Alpes region. Data were collected by a self-questionnaire in 2016. Sterilization procedures (n = 33) were classified into 4 groups: (1) Pre-sterilization cleaning of reusable instruments; (2) Biological verification of sterilization cycles—Monitoring steam sterilization procedures; (3) Autoclave performance and practitioner knowledge of autoclave use; (4) Monitoring and documentation of sterilization procedures—Tracking and tracing the instrumentation. Answers were provided per procedure, along with the global implementation of procedures within a group (over 80% correctly performed). Then it was verified how adherence to procedure groups varied with the size of the dental practice and the proportion of dental assistants within the team. Among the 179 questionnaires available for the analyses, adherence to the recommended procedures of sterilization noticeably varied between practices, from 20.7% to 82.6%. The median percentages of procedures correctly implemented per practice were 58.1%, 50.9%, 69.2% and 58.2%, in Groups 1, 2, 3 and 4, respectively (corresponding percentages for performing over 80% of the procedures in the group: 23.4%, 6.6%, 46.6% and 38.6%). Dental practices ≥ 3 dental units performed significantly better (>80%) procedures of Groups 2 and 4 (p = 0.01 and p = 0.002, respectively), while no other significant associations emerged. As a rule, practices complied poorly with the recommended procedures, despite partially improved results in bigger practices. Specific training regarding sterilization procedures and a better understanding of the reasons leading to their non-compliance are needed. PMID:29693615

Gerstmann-Straeussler-Scheinker disease with P102L prion protein gene mutation presenting with rapidly progressive clinical course.

PubMed

Iwasaki, Yasushi; Mori, Keiko; Ito, Masumi; Nokura, Kazuya; Tatsumi, Shinsui; Mimuro, Maya; Kitamoto, Tetsuyuki; Yoshida, Mari

2014-01-01

We describe an autopsied case of a Japanese woman with Gerstmann-Straeussler-Scheinker disease (GSS) presenting with a rapidly progressive clinical course. Disease onset occurred at the age of 54 with dementia and gait disturbance. Her clinical course progressively deteriorated until she reached a bedridden state with myoclonus 9 months after onset. Two months later, she reached the akinetic mutism state. Nasal tube feeding was introduced at this point and continued for several years. Electroencephalograms showed diffuse slowing without periodic sharp-wave complexes. Diffusion-weighted magnetic resonance imaging (MRI) showed widespread cerebral cortical hyperintensity. Prion protein (PrP) gene analysis revealed a Pro to Leu point mutation at codon 102 with methionine homozygosity at codon 129. The patient died of respiratory failure after a total disease duration of 62 months. Neuropathologic examination revealed widespread spongiform change with numerous eosinophilic amyloid plaques (Kuru plaques) in the cerebral and cerebellar cortices by H & E staining. Diffuse myelin pallor with axon loss of the cerebral white matter, suggestive of panencephalopathic-type pathology was observed. Numerous PrP immunopositive plaques and diffuse synaptic-type PrP deposition were extensively observed, particularly in the cerebral and cerebellar cortices. Western blot analysis of proteinase Kresistant PrP showed a characteristic band pattern with a small molecular band of 6 kDa. The reason for the similarity in clinicopathologic findings between the present case and Creutzfeldt-Jakob disease is uncertain; however, the existence of an unknown disease-modifying factor is suspected.

Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases?

PubMed

Bellingham, Shayne A; Guo, Belinda B; Coleman, Bradley M; Hill, Andrew F

2012-01-01

Exosomes are small membranous vesicles secreted by a number of cell types including neurons and can be isolated from conditioned cell media or bodily fluids such as urine and plasma. Exosome biogenesis involves the inward budding of endosomes to form multivesicular bodies (MVB). When fused with the plasma membrane, the MVB releases the vesicles into the extracellular environment as exosomes. Proposed functions of these vesicles include roles in cell-cell signaling, removal of unwanted proteins, and the transfer of pathogens between cells. One such pathogen which exploits this pathway is the prion, the infectious particle responsible for the transmissible neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) of humans or bovine spongiform encephalopathy (BSE) of cattle. Similarly, exosomes are also involved in the processing of the amyloid precursor protein (APP) which is associated with Alzheimer's disease. Exosomes have been shown to contain full-length APP and several distinct proteolytically cleaved products of APP, including Aβ. In addition, these fragments can be modulated using inhibitors of the proteases involved in APP cleavage. These observations provide further evidence for a novel pathway in which PrP and APP fragments are released from cells. Other proteins such as superoxide dismutase I and alpha-synuclein (involved in amyotrophic lateral sclerosis and Parkinson's disease, respectively) are also found associated with exosomes. This review will focus on the role of exosomes in neurodegenerative disorders and discuss the potential of these vesicles for the spread of neurotoxicity, therapeutics, and diagnostics for these diseases.

A brief history of prions.

PubMed

Zabel, Mark D; Reid, Crystal

2015-12-01

Proteins were described as distinct biological molecules and their significance in cellular processes was recognized as early as the 18th century. At the same time, Spanish shepherds observed a disease that compelled their Merino sheep to pathologically scrape against fences, a defining clinical sign that led to the disease being named scrapie. In the late 19th century, Robert Koch published his postulates for defining causative agents of disease. In the early 20th century, pathologists Creutzfeldt and Jakob described a neurodegenerative disease that would later be included with scrapie into a group of diseases known as transmissible spongiform encephalopathies (TSEs). Later that century, mounting evidence compelled a handful of scientists to betray the prevailing biological dogma governing pathogen replication that Watson and Crick so convincingly explained by cracking the genetic code just two decades earlier. Because TSEs seemed to defy these new rules, J.S. Griffith theorized mechanisms by which a pathogenic protein could encipher its own replication blueprint without a genetic code. Stanley Prusiner called this proteinaceous infectious pathogen a prion. Here we offer a concise account of the discovery of prions, the causative agent of TSEs, in the wider context of protein biochemistry and infectious disease. We highlight the discovery of prions in yeast and discuss the implication of prions as epigenomic carriers of biological and pathological information. We also consider expanding the prion hypothesis to include other proteins whose alternate isoforms confer new biological or pathological properties. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A brief history of prions

PubMed Central

Zabel, Mark D.; Reid, Crystal

2015-01-01

Proteins were described as distinct biological molecules and their significance in cellular processes was recognized as early as the 18th century. At the same time, Spanish shepherds observed a disease that compelled their Merino sheep to pathologically scrape against fences, a defining clinical sign that led to the disease being named scrapie. In the late 19th century, Robert Koch published his postulates for defining causative agents of disease. In the early 20th century, pathologists Creutzfeldt and Jakob described a neurodegenerative disease that would later be included with scrapie into a group of diseases known as transmissible spongiform encephalopathies (TSEs). Later that century, mounting evidence compelled a handful of scientists to betray the prevailing biological dogma governing pathogen replication that Watson and Crick so convincingly explained by cracking the genetic code just two decades earlier. Because TSEs seemed to defy these new rules, J.S. Griffith theorized mechanisms by which a pathogenic protein could encipher its own replication blueprint without a genetic code. Stanley Prusiner called this proteinaceous infectious pathogen a prion. Here we offer a concise account of the discovery of prions, the causative agent of TSEs, in the wider context of protein biochemistry and infectious disease. We highlight the discovery of prions in yeast and discuss the implication of prions as epigenomic carriers of biological and pathological information. We also consider expanding the prion hypothesis to include other proteins whose alternate isoforms confer new biological or pathological properties. PMID:26449713

From mad cows to sensible blood transfusion: the risk of prion transmission by labile blood components in the United Kingdom and in France.

PubMed

Lefrère, Jean-Jacques; Hewitt, Patricia

2009-04-01

Transfusion transmission of the prion, the agent of variant Creutzfeldt-Jakob disease (vCJD), is now established. Subjects infected through food may transmit the disease through blood donations. The two nations most affected to date by this threat are the United Kingdom (UK) and France. The first transfusion cases have been observed in the UK over the past 5 years. In France, a few individuals who developed vCJD had a history of blood donation, leading to a risk of transmission to recipients, some of whom could be incubating the disease. In the absence of a large-scale screening test, it is impossible to establish the prevalence of infection in the blood donor population and transfused patients. This lack of a test also prevents specific screening of blood donations. Thus, prevention of transfusion transmission essentially relies at present on deferral of "at-risk" individuals. Because prions are present in both white blood cells and plasma, leukoreduction is probably insufficient to totally eliminate the transfusion risk. In the absence of a screening test for blood donations, recently developed prion-specific filters could be a solution. Furthermore, while the dietary spread of vCJD seems efficiently controlled, uncertainty remains as to the extent of the spread of prions through blood transfusion and other secondary routes.

Exploring the early steps of aggregation of amyloid-forming peptide KFFE

NASA Astrophysics Data System (ADS)

Wei, Guanghong; Mousseau, Normand; Derreumaux, Philippe

2004-11-01

It has been shown recently that even a tetrapeptide can form amyloid fibrils sharing all the characteristics of amyloid fibrils built from large proteins. Recent experimental studies also suggest that the toxicity observed in several neurodegenerative diseases, such as Alzheimer's disease and Creutzfeldt-Jakob disease, is not only related to the mature fibrils themselves, but also to the soluble oligomers formed early in the process of fibrillogenesis. This raises the interest in studying the early steps of the aggregation process. Although fibril formation follows the nucleation-condensation process, characterized by the presence of lag phase, the exact pathways remain to be determined. In this study, we used the activation-relaxation technique and a generic energy model to explore the process of self-assembly and the structures of the resulting aggregates of eight KFFE peptides. Our simulations show, starting from different states with a preformed antiparallel dimer, that eight chains can self-assemble to adopt, with various orientations, four possible distant oligomeric well-aligned structures of similar energy. Two of these structures show a double-layer β-sheet organization, in agreement with the structure of amyloid fibrils as observed by x-ray diffraction; another two are mixtures of dimers and trimers. Our results also suggest that octamers are likely to be below the critical size for nucleation of amyloid fibrils for small peptides.

[Human transmissible subacute spongiform encephalopathy].

PubMed

Dormont, D

1994-05-01

Human transmissible spongiform encephalopathies (TSE) are rare chronic subacute degenerative diseases of the central nervous system (CNS) which include Creutzfeldt-Jakob disease (CJD), Kuru, Gerstmann-Sträussler-Scheinker syndrome (GSS), and Fatal Familial Insomnia (FFI). CJD can be either inherited or sporadic. All these diseases are always fatal. Neuropathological features are mainly constituted of neuronal vacuolisation, neuronal death, gliosis with hyperastrocytosis; plaques might be evidenced in kuru and GSS. Neither inflammatory syndrome nor demyelination is detectable. No virus like structure could be identified reproducibly. Human TSE are transmissible to non human primates and rodents. Iatrogenic CJD have been described after tissue grafting (cornea, dura mater), neurosurgery, electrophysiology investigation, and treatment with pituitary derived gonadotrophins and growth hormone. Molecular biochemistry of the CNS investigation revealed that a host encoded protein, the prion protein (PrP), accumulates proportionally to the infectious titer: this abnormality is the only detectable hallmark in TSE. Infectious fractions contain no detectable specific nucleic acid, and are mainly constituted of PrP under an isoform which resists to proteinase K digestion (PrP-res). The PrP gene (PRNP) is located on chromosome 20 in humans. Several mutations of this gene have been described in all inherited TSE (CJD, GSS, and IFF). No treatment is available today. Agents inducing TSE (TSA) are not known: several authors claim that TSA are only constituted of PrP-res; others support the hypothesis of a conventional agent with a specific genetic information.

Adult dementia: history, biopsy, pathology.

PubMed

Torack, R M

1979-05-01

The historical events in the evolution of Alzheimer's disease are reviewed, including the initial description by Alois Alzheimer and the subsequent controversy regarding the nosological specificity of this entity. The similarity of senile dementia and Alzheimer's disease is emphasized. The basis for the modern concept of Alzheimer's disease as premature or accelerated aging is included in the review. The pathological correlates of the major categories of adult dementia have been described. The traditional criteria of neurofibrillary tangles and senile plaques have been re-evaluated using the current insight into these changes afforded by electron microscopy and biochemistry. The significance of amyloid has been described because it occurs within the senile plaque and also as the essential component of congophilic angiopathy. The new information regarding neuronal cell counts and the loss of choline acetyltransferase has been evaluated in terms of an indication of a pathogenic mechanism of Alzheimer's disease. The current understanding of normal pressure hydrocephalus, Creutzfeldt-Jakob disease, and multi-infarct dementia has been described. Brain biopsy in dementia has been described as having diagnostic, research, pathogenic, and prognostic value. The precautions involving the performance and handling of the biopsy have been stressed, particularly because these procedures involve conditions of possible slow virus etiology. The polemic for Alzheimer's disease as aging or slow virus infection has been summarized. At this time a consideration seems justified that Alzheimer's disease is an age-related, slow virus disease due to a hitherto unknown immune defect. Aging as an etiological agent must be clarified before Alzheimer's disease, in any form, can be considered to be an inevitable consequence of longevity.

Variably Protease-Sensitive Prionopathy: A New Sporadic Disease of the Prion Protein

PubMed Central

Zou, Wen-Quan; Puoti, Gianfranco; Xiao, Xiangzhu; Yuan, Jue; Qing, Liuting; Cali, Ignazio; Shimoji, Miyuki; Langeveld, Jan P. M.; Castellani, Rudy; Notari, Silvio; Crain, Barbara; Schmidt, Robert E.; Geschwind, Michael; DeArmond, Stephen J.; Cairns, Nigel J.; Dickson, Dennis; Honig, Lawrence; Torres, Juan Maria; Mastrianni, James; Capellari, Sabina; Giaccone, Giorgio; Belay, Ermias D.; Schonberger, Lawrence B.; Cohen, Mark; Perry, George; Kong, Qingzhong; Parchi, Piero; Tagliavini, Fabrizio; Gambetti, Pierluigi

2011-01-01

Objective The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV). Methods Fifteen affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics. Results Disease duration (between 22 and 45 months) was significantly different in the 129VV and 129MV subjects. Most other phenotypic features along with the PrP electrophoretic profile were similar but distinguishable in the 3 129 genotypes. A major difference laid in the sensitivity to protease digestion of the disease-associated PrP, which was high in 129VV but much lower, or altogether lacking, in 129MV and 129MM. This difference prompted the substitution of the original designation with “variably protease-sensitive prionopathy” (VPSPr). None of the subjects had mutations in the PrP gene coding region. Interpretation Because all 3 129 genotypes are involved, and are associated with distinguishable phenotypes, VPSPr becomes the second sporadic prion protein disease with this feature after Creutzfeldt-Jakob disease, originally reported in 1920. However, the characteristics of the abnormal prion protein suggest that VPSPr is different from typical prion diseases, and perhaps more akin to subtypes of Gerstmann-Sträussler-Scheinker disease. PMID:20695009

Social and environmental risk factors in the emergence of infectious diseases.

PubMed

Weiss, Robin A; McMichael, Anthony J

2004-12-01

Fifty years ago, the age-old scourge of infectious disease was receding in the developed world in response to improved public health measures, while the advent of antibiotics, better vaccines, insecticides and improved surveillance held the promise of eradicating residual problems. By the late twentieth century, however, an increase in the emergence and re-emergence of infectious diseases was evident in many parts of the world. This upturn looms as the fourth major transition in human-microbe relationships since the advent of agriculture around 10,000 years ago. About 30 new diseases have been identified, including Legionnaires' disease, human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), hepatitis C, bovine spongiform encephalopathy (BSE)/variant Creutzfeldt-Jakob disease (vCJD), Nipah virus, several viral hemorrhagic fevers and, most recently, severe acute respiratory syndrome (SARS) and avian influenza. The emergence of these diseases, and resurgence of old ones like tuberculosis and cholera, reflects various changes in human ecology: rural-to-urban migration resulting in high-density peri-urban slums; increasing long-distance mobility and trade; the social disruption of war and conflict; changes in personal behavior; and, increasingly, human-induced global changes, including widespread forest clearance and climate change. Political ignorance, denial and obduracy (as with HIV/AIDS) further compound the risks. The use and misuse of medical technology also pose risks, such as drug-resistant microbes and contaminated equipment or biological medicines. A better understanding of the evolving social dynamics of emerging infectious diseases ought to help us to anticipate and hopefully ameliorate current and future risks.

Pathogenic prion protein fragment (PrP106-126) promotes human immunodeficiency virus type-1 infection in peripheral blood monocyte-derived macrophages.

PubMed

Bacot, Silvia M; Feldman, Gerald M; Yamada, Kenneth M; Dhawan, Subhash

2015-02-01

Transfusion of blood and blood products contaminated with the pathogenic form of prion protein Prp(sc), thought to be the causative agent of variant a Creutzfeldt-Jakob disease (vCJD), may result in serious consequences in recipients with a compromised immune system, for example, as seen in HIV-1 infection. In the present study, we demonstrate that treatment of peripheral blood monocyte-derived macrophages (MDM) with PrP106-126, a synthetic domain of PrP(sc) that has intrinsic functional activities related to the full-length protein, markedly increased their susceptibility to HIV-1 infection, induced cytokine secretion, and enhanced their migratory behavior in response to N-formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLP). Live-cell imaging of MDM cultured in the presence of PrP106-126 showed large cell clusters indicative of cellular activation. Tyrosine kinase inhibitor STI-571, protein kinase C inhibitor K252B, and cyclin-dependent kinase inhibitor olomoucine attenuated PrP106-126-induced altered MDM functions. These findings delineate a previously undefined functional role of PrP106-126-mediated host cell response in promoting HIV-1 pathogenesis. Published by Elsevier Inc.

Kinetics of autocatalysis in small systems

NASA Astrophysics Data System (ADS)

Arslan, Erdem; Laurenzi, Ian J.

2008-01-01

Autocatalysis is a ubiquitous chemical process that drives a plethora of biological phenomena, including the self-propagation of prions etiological to the Creutzfeldt-Jakob disease and bovine spongiform encephalopathy. To explain the dynamics of these systems, we have solved the chemical master equation for the irreversible autocatalytic reaction A +B→2A. This solution comprises the first closed form expression describing the probabilistic time evolution of the populations of autocatalytic and noncatalytic molecules from an arbitrary initial state. Grand probability distributions are likewise presented for autocatalysis in the equilibrium limit (A+B⇌2A), allowing for the first mechanistic comparison of this process with chemical isomerization (B⇌A) in small systems. Although the average population of autocatalytic (i.e., prion) molecules largely conforms to the predictions of the classical "rate law" approach in time and the law of mass action at equilibrium, thermodynamic differences between the entropies of isomerization and autocatalysis are revealed, suggesting a "mechanism dependence" of state variables for chemical reaction processes. These results demonstrate the importance of chemical mechanism and molecularity in the development of stochastic processes for chemical systems and the relationship between the stochastic approach to chemical kinetics and nonequilibrium thermodynamics.

Molecular mechanisms of chronic wasting disease prion propagation

PubMed Central

Moreno, Julie A.; Telling, Glenn C.

2018-01-01

Prion disease epidemics, which have been unpredictable recurrences, are of significant concern for animal and human health. Examples include kuru, once the leading cause of death among the Fore people in Papua New Guinea and caused by mortuary feasting; bovine spongiform encephalopathy (BSE) and its subsequent transmission to humans in the form of variant Creutzfeldt-Jakob disease (vCJD); and repeated examples of large-scale prion disease epidemics in animals caused by contaminated vaccines. The etiology of chronic wasting disease (CWD), a relatively new and burgeoning prion epidemic in deer, elk, and moose (members of the cervid family), is more enigmatic. The disease was first described in captive and later in wild mule deer and subsequently in free-ranging as well as captive Rocky Mountain elk, white-tailed deer, and most recently moose. It is therefore the only recognized prion disorder of both wild and captive animals. In addition to its expanding range of hosts, CWD continues to spread to new geographical areas, including recent cases in Norway. The unparalleled efficiency of the contagious transmission of the disease combined with high densities of deer in certain areas of North America complicates strategies for controlling CWD and raises concerns about its potential spread to new species. Because there is a high prevalence of CWD in deer and elk, which are commonly hunted and consumed by humans, the possibility of zoonotic transmission is particularly concerning. Here we review the current status of naturally occurring CWD and describe advances in our understanding of its molecular pathogenesis, as shown by studies of CWD prions in novel in vivo and in vitro systems. PMID:28193766

Studies of the aggregation of mutant proteins in vitro provide insights into the genetics of amyloid diseases.

PubMed

Chiti, Fabrizio; Calamai, Martino; Taddei, Niccolo; Stefani, Massimo; Ramponi, Giampietro; Dobson, Christopher M

2002-12-10

Protein aggregation and the formation of highly insoluble amyloid structures is associated with a range of debilitating human conditions, which include Alzheimer's disease, Parkinson's disease, and the Creutzfeldt-Jakob disease. Muscle acylphosphatase (AcP) has already provided significant insights into mutational changes that modulate amyloid formation. In the present paper, we have used this system to investigate the effects of mutations that modify the charge state of a protein without affecting significantly the hydrophobicity or secondary structural propensities of the polypeptide chain. A highly significant inverse correlation was found to exist between the rates of aggregation of the protein variants under denaturing conditions and their overall net charge. This result indicates that aggregation is generally favored by mutations that bring the net charge of the protein closer to neutrality. In light of this finding, we have analyzed natural mutations associated with familial forms of amyloid diseases that involve alteration of the net charge of the proteins or protein fragments associated with the diseases. Sixteen mutations have been identified for which the mechanism of action that causes the pathological condition is not yet known or fully understood. Remarkably, 14 of these 16 mutations cause the net charge of the corresponding peptide or protein that converts into amyloid deposits to be reduced. This result suggests that charge has been a key parameter in molecular evolution to ensure the avoidance of protein aggregation and identifies reduction of the net charge as an important determinant in at least some forms of protein deposition diseases.

[Still a small problem with the mad cow disease? Creutzfeldt-Jakob disease and other prion diseases: current status].

PubMed

Lundberg, P O

2001-01-10

This review is based on recent published research on the BSE/CJD/vCJD problem mainly from UK, Germany and France. The situation in Sweden seems to be fortunate for several reasons. The use of meat and bonemeal as animal fodder was forbidden in this country 13 years ago. Sweden has not had any sheep with scrapie for many years. No animals with BSE have so far been found in our country. The incidence of sporadic CJD in this country followed retrospectively from 1985 to 1996 and prospectively from 1997 to 1999 has been around 1.2 per million per year with no significant increase. Only few cases of familial CJD are known. No patient with iatrogenic CJD has ever been found. The use of growth hormone derived from human pituitary glands was abandoned in 1985 when recombinant human growth hormone became available. So far there is no indication that any of the CJD cases diagnosed in Sweden has been of the vCJD type, the one linked to BSE. However, as the incubation period for prion diseases is very long and the Swedes are frequent travellers there is a risk that people from our country could have contracted vCJD through consuming meat products in countries with BSE. As a precaution the consumption of brain, spinal cord, lymphatic tissue, lungs, and gastrointestinal tract should be avoided. Human pituitary derived growth hormone is still available in some countries and might be illegally imported into Sweden.

Overexpression of the Hspa13 (Stch) gene reduces prion disease incubation time in mice.

PubMed

Grizenkova, Julia; Akhtar, Shaheen; Hummerich, Holger; Tomlinson, Andrew; Asante, Emmanuel A; Wenborn, Adam; Fizet, Jérémie; Poulter, Mark; Wiseman, Frances K; Fisher, Elizabeth M C; Tybulewicz, Victor L J; Brandner, Sebastian; Collinge, John; Lloyd, Sarah E

2012-08-21

Prion diseases are fatal neurodegenerative disorders that include bovine spongiform encephalopathy (BSE) and scrapie in animals and Creutzfeldt-Jakob disease (CJD) in humans. They are characterized by long incubation periods, variation in which is determined by many factors including genetic background. In some cases it is possible that incubation time may be directly correlated to the level of gene expression. To test this hypothesis, we combined incubation time data from five different inbred lines of mice with quantitative gene expression profiling in normal brains and identified five genes with expression levels that correlate with incubation time. One of these genes, Hspa13 (Stch), is a member of the Hsp70 family of ATPase heat shock proteins, which have been previously implicated in prion propagation. To test whether Hspa13 plays a causal role in determining the incubation period, we tested two overexpressing mouse models. The Tc1 human chromosome 21 (Hsa21) transchromosomic mouse model of Down syndrome is trisomic for many Hsa21 genes including Hspa13 and following Chandler/Rocky Mountain Laboratory (RML) prion inoculation, shows a 4% reduction in incubation time. Furthermore, a transgenic model with eightfold overexpression of mouse Hspa13 exhibited highly significant reductions in incubation time of 16, 15, and 7% following infection with Chandler/RML, ME7, and MRC2 prion strains, respectively. These data further implicate Hsp70-like molecular chaperones in protein misfolding disorders such as prion disease.

Amplified Detection of Prions and Other Amyloids by RT-QuIC in Diagnostics and the Evaluation of Therapeutics and Disinfectants.

PubMed

Caughey, Byron; Orru, Christina D; Groveman, Bradley R; Hughson, Andrew G; Manca, Matteo; Raymond, Lynne D; Raymond, Gregory J; Race, Brent; Saijo, Eri; Kraus, Allison

2017-01-01

Among the most sensitive, specific and practical of methods for detecting prions are the real-time quaking-induced conversion (RT-QuIC) assays. These assays exploit the fundamental self-propagating activity of prions to amplify the presence of prion seeds by as much as a trillion-fold. The reactions can detect most of the known mammalian prion diseases, often with sensitivities greater than those of animal bioassays. RT-QuIC assays are performed in multiwell plates with fluorescence detection and have now reached the sensitivity and practicality required for routine prion disease diagnostics. Some key strains of prions within particular host species, e.g., humans, cattle, and sheep, can be discriminated by comparison of RT-QuIC responses with different recombinant prion protein substrates. The most thoroughly validated diagnostic application of RT-QuIC is in the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) using cerebrospinal fluid. Diagnostic sensitivities as high as 96% can be achieved in less than 24h with specificities of 98%-100%. The ability, if needed, to also test nasal swab samples can increase the RT-QuIC sensitivity for sCJD to virtually 100%. In addition to diagnostic applications, RT-QuIC has also been used in the testing of prion disinfectants and potential therapeutics. Mechanistically related assays are also now being developed for other protein misfolding diseases. © 2017 Elsevier Inc. All rights reserved.

Intact protein analysis of ubiquitin in cerebrospinal fluid by multiple reaction monitoring reveals differences in Alzheimer's disease and frontotemporal lobar degeneration.

PubMed

Oeckl, Patrick; Steinacker, Petra; von Arnim, Christine A F; Straub, Sarah; Nagl, Magdalena; Feneberg, Emily; Weishaupt, Jochen H; Ludolph, Albert C; Otto, Markus

2014-11-07

The impairment of the ubiquitin-proteasome system (UPS) is thought to be an early event in neurodegeneration, and monitoring UPS alterations might serve as a disease biomarker. Our aim was to establish an alternate method to antibody-based assays for the selective measurement of free monoubiquitin in cerebrospinal fluid (CSF). Free monoubiquitin was measured with liquid chromatography-multiple reaction monitoring mass spectrometry (LC-MS/MS) in CSF of patients with Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), behavioral variant of frontotemporal dementia (bvFTD), Creutzfeldt-Jakob disease (CJD), Parkinson's disease (PD), primary progressive aphasia (PPA), and progressive supranuclear palsy (PSP). The LC-MS/MS method showed excellent intra- and interassay precision (4.4-7.4% and 4.9-10.3%) and accuracy (100-107% and 100-106%). CSF ubiquitin concentration was increased compared with that of controls (33.0 ± 9.7 ng/mL) in AD (47.5 ± 13.1 ng/mL, p < 0.05) and CJD patients (171.5 ± 103.5 ng/mL, p < 0.001) but not in other neurodegenerative diseases. Receiver operating characteristic curve (ROC) analysis of AD vs control patients revealed an area under the curve (AUC) of 0.832, and the specificity and sensitivity were 75 and 75%, respectively. ROC analysis of AD and FTLD patients yielded an AUC of 0.776, and the specificity and sensitivity were 53 and 100%, respectively. In conclusion, our LC-MS/MS method may facilitate ubiquitin determination to a broader community and might help to discriminate AD, CJD, and FTLD patients.

Epidemiology of early-onset dementia: a review of the literature

PubMed Central

Vieira, Renata Teles; Caixeta, Leonardo; Machado, Sergio; Silva, Adriana Cardoso; Nardi, Antonio Egidio; Arias-Carrión, Oscar; Carta, Mauro Giovanni

2013-01-01

Presenile Dementia or Early Onset Dementia (EOD) is a public health problem, it differs from Senile Dementia, and encloses a significant number of cases; nevertheless, it is still poorly understood and underdiagnosed. This study aims to review the prevalence and etiology of EOD, comparing EOD with Senile Dementia, as well as to show the main causes of EOD and their prevalence in population and non-population based studies. The computer-supported search used the following databases: Pubmed/Medline, ISI Web of Knowledge and Scielo. The search terms were alcohol-associated dementia, Alzheimer’s disease, dementia, Creutzfeldt-jakob disease, dementia with lewy bodies, early onset dementia, frontotemporal lobar degeneration, Huntington’s disease, mixed dementia, neurodegenerative disorders, Parkinson’s disease dementia, presenile dementia, traumatic brain injury, vascular dementia. Only papers published in English and conducted from 1985 up to 2012 were preferentially reviewed. Neurodegenerative diseases are the most common etiologies seen in EOD. Among the general population, the prevalence of EOD was found to range between 0 to 700 per 100.000 habitants in groups of 25-64 years old, with an increasing incidence with age. The progression of EOD was found to range between 8.3 to 22.8 new cases per 100.000 in those aged under 65 years. Alzheimer's disease (AD) is the major etiology, followed by Vascular Dementia (VaD) and Frontotemporal Lobar Degeneration (FTLD). A larger number of epidemiological studies to elucidate how environmental issues contribute to EOD are necessary, thus, we can collaborate in the planning and prevention of services toward dementia patients. PMID:23878613

Prion Disease Induces Alzheimer Disease-Like Neuropathologic Changes

PubMed Central

Tousseyn, Thomas; Bajsarowicz, Krystyna; Sánchez, Henry; Gheyara, Ania; Oehler, Abby; Geschwind, Michael; DeArmond, Bernadette; DeArmond, Stephen J.

2016-01-01

We examined the brains of 266 patients with prion diseases (PrionD) and found that 46 (17%) had Alzheimer disease (AD)-like changes. To explore potential mechanistic links between PrionD and AD, we exposed human brain aggregates (Hu BrnAggs) to brain homogenate from a patient with sporadic Creutzfeldt-Jakob disease (CJD) and found that the neurons in the Hu BrnAggs produced many β-amyloid (β42) inclusions, whereas uninfected, control-exposed Hu BrnAggs did not. Western blots of 20-pooled CJD-infected BrnAggs verified higher Aβ42 levels than controls. We next examined the CA1 region of the hippocampus from 14 patients with PrionD and found that 5 patients had low levels of scrapie-associated prion protein (PrPSc), many Aβ42 intraneuronal inclusions, low APOE-4, and no significant nerve cell loss. Seven patients had high levels of PrPSc, low Aβ42, high APOE-4 and 40% nerve cell loss, suggesting that APOE-4 and PrPSc together cause neuron loss in PrionD. There were also increased levels of hyperphosphorylated tau protein (Hτ) and Hτ-positive neuropil threads and neuron bodies in both PrionD and AD groups. The brains of 6 age-matched control patients without dementia did not contain Aβ42 deposits; however, there were rare Hτ-positive threads in 5 controls and 2 controls had a few Hτ-positive nerve cell bodies. We conclude that PrionD may trigger biochemical changes similar to AD and suggest that PrionD are diseases of PrPSc, Aβ42, APOE-4 and abnormal tau. PMID:26226132

Bank Vole Prion Protein As an Apparently Universal Substrate for RT-QuIC-Based Detection and Discrimination of Prion Strains.

PubMed

Orrú, Christina D; Groveman, Bradley R; Raymond, Lynne D; Hughson, Andrew G; Nonno, Romolo; Zou, Wenquan; Ghetti, Bernardino; Gambetti, Pierluigi; Caughey, Byron

2015-06-01

Prions propagate as multiple strains in a wide variety of mammalian species. The detection of all such strains by a single ultrasensitive assay such as Real Time Quaking-induced Conversion (RT-QuIC) would facilitate prion disease diagnosis, surveillance and research. Previous studies have shown that bank voles, and transgenic mice expressing bank vole prion protein, are susceptible to most, if not all, types of prions. Here we show that bacterially expressed recombinant bank vole prion protein (residues 23-230) is an effective substrate for the sensitive RT-QuIC detection of all of the different prion types that we have tested so far--a total of 28 from humans, cattle, sheep, cervids and rodents, including several that have previously been undetectable by RT-QuIC or Protein Misfolding Cyclic Amplification. Furthermore, comparison of the relative abilities of different prions to seed positive RT-QuIC reactions with bank vole and not other recombinant prion proteins allowed discrimination of prion strains such as classical and atypical L-type bovine spongiform encephalopathy, classical and atypical Nor98 scrapie in sheep, and sporadic and variant Creutzfeldt-Jakob disease in humans. Comparison of protease-resistant RT-QuIC conversion products also aided strain discrimination and suggested the existence of several distinct classes of prion templates among the many strains tested.

Balancing evidence and public opinion in health technology assessments: the case of leukoreduction.

PubMed

Cleemput, Irina; Leys, Mark; Ramaekers, Dirk; Bonneux, Luc

2006-01-01

Leukoreduction, filtering white blood cells from transfusion blood, effectively avoids leukocyte-related complications of blood transfusion. The technology has proven its relative cost-effectiveness for specific patient populations. With the advent of variant Creutzfeldt-Jakob disease, a transmittable spongiform encephalopathy caused by mad cow disease (bovine spongiform encephalopathy), the hard hit United Kingdom introduced universal leukoreduction for all patients as a precaution for transmission of prions in 1999. This costly policy was followed by many other countries, in the absence of much evidence of an actual health problem or of a more than presumed effectiveness of leukoreduction in preventing prion transmission. The core problem proved to be legal. The blood banks are legally accountable for blood safety. This accountability is absolute, based on avoidance of all possible risks, regardless of costs. This strategy leads to inefficiencies in health care: (i) blood safety management is guided by available rather than cost-effective technology, and (ii) private insurance premiums for civil liability are sharply increasing, while they are in no way related to the expected returns and the high and increasing blood safety. A rational safety policy is to be optimal, taking into account costs and effects of the safety procedures. This issue will need an open discussion with the general public of the real risks and a clear and unambiguous definition of proportionality in the precautionary principle, based on the European law.

Ascertainment Bias Causes False Signal of Anticipation in Genetic Prion Disease

PubMed Central

Minikel, Eric Vallabh; Zerr, Inga; Collins, Steven J.; Ponto, Claudia; Boyd, Alison; Klug, Genevieve; Karch, André; Kenny, Joanna; Collinge, John; Takada, Leonel T.; Forner, Sven; Fong, Jamie C.; Mead, Simon; Geschwind, Michael D.

2014-01-01

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. PMID:25279981

A naturally occurring variant of the human prion protein completely prevents prion disease.

PubMed

Asante, Emmanuel A; Smidak, Michelle; Grimshaw, Andrew; Houghton, Richard; Tomlinson, Andrew; Jeelani, Asif; Jakubcova, Tatiana; Hamdan, Shyma; Richard-Londt, Angela; Linehan, Jacqueline M; Brandner, Sebastian; Alpers, Michael; Whitfield, Jerome; Mead, Simon; Wadsworth, Jonathan D F; Collinge, John

2015-06-25

Mammalian prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP). A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru--an acquired prion disease epidemic of the Fore population in Papua New Guinea--and appeared to provide strong protection against disease in the heterozygous state. Here we have investigated the protective role of this variant and its interaction with the common, worldwide M129V PrP polymorphism. V127 was seen exclusively on a M129 PRNP allele. We demonstrate that transgenic mice expressing both variant and wild-type human PrP are completely resistant to both kuru and classical Creutzfeldt-Jakob disease (CJD) prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to bovine spongiform encephalopathy prions to which the Fore were not exposed. Notably, mice expressing only PrP V127 were completely resistant to all prion strains, demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and kuru in the heterozygous state. Indeed, this single amino acid substitution (G→V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wild-type PrP indicates that not only is PrP V127 completely refractory to prion conversion but acts as a potent dose-dependent inhibitor of wild-type prion propagation.

R3-R4 deletion in the PRNP gene is associated with Creutzfeldt-Jakob disease (CJD)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cervenakova, L.; Brown, P.; Nagle, J.

1994-09-01

There are conflicting reports on the association of deletions in the PRNP gene on chromosome 20 with CJD, a rapidly progressive fatal spongiform encephalopathy. We accumulated data suggesting that a deletion of R3-R4 type (parts of the third and fourth repeats are deleted from the area of four repeating 24 bp sequences in the 5{prime} region of the gene) is causing CJD. Screening of 129 unaffected control individuals demonstrated presence of a deletion of R2 type in four (1.55% of the studied chromosomes), but none of them had the R3-R4 type. Of 181 screened patients with spongiform encephalopathies, two hadmore » a deletion of R3-R4 type with no other mutations in the coding sequence. Both patients had a classical rapidly progressive dementing disease and diffuse spongiform degeneration, and both cases were apparently sporadic. The same R3-R4 type of deletion was detected in three additional neuropathologically confirmed spongiform encephalopathy patients, of which two had other known pathogenic mutations in the PRNP gene: at codon 178 on the methionine allele exhibiting the phenotype of fatal familial insomnia, and codon 200 causing CJD with severe dementia; the third was a patient with iatrogenic CJD who developed the disease after treatment with growth hormone extracted from cadaveric human pituitary glands. In all cases the deletion coincided with a variant sequence at position 129 coding for methionine.« less

Benzothiazole Aniline Tetra(ethylene glycol) and 3-Amino-1,2,4-triazole Inhibit Neuroprotection against Amyloid Peptides by Catalase Overexpression in Vitro

PubMed Central

2013-01-01

Alzheimer’s disease, Familial British dementia, Familial Danish dementia, Type 2 diabetes mellitus, plus Creutzfeldt-Jakob disease are associated with amyloid fibril deposition and oxidative stress. The antioxidant enzyme catalase is a neuroprotective amyloid binding protein. Herein the effects of catalase overexpression in SH-SY5Y neuronal cells on the toxicity of amyloid-β (Aβ), amyloid-Bri (ABri), amyloid-Dan (ADan), amylin (IAPP), and prion protein (PrP) peptides were determined. Results showed catalase overexpression was neuroprotective against Aβ, ABri, ADan, IAPP, and PrP peptides. The catalase inhibitor 3-amino-1,2,4-triazole (3-AT) and catalase-amyloid interaction inhibitor benzothiazole aniline tetra(ethylene glycol) (BTA-EG4) significantly enhanced neurotoxicity of amyloid peptides in catalase overexpressing neuronal cells. This suggests catalase neuroprotection involves breakdown of hydrogen peroxide (H2O2) plus a direct binding interaction between catalase and the Aβ, ABri, ADan, IAPP, and PrP peptides. Kisspeptin 45–50 had additive neuroprotective actions against the Aβ peptide in catalase overexpressing cells. The effects of 3-AT had an intracellular site of action, while catalase-amyloid interactions had an extracellular component. These results suggest that the 3-AT and BTA-EG4 compounds may be able to inhibit endogenous catalase mediated neuroprotection. Use of BTA-EG4, or compounds that inhibit catalase binding to amyloid peptides, as potential therapeutics for Neurodegenerative diseases may therefore result in unwanted effects. PMID:23968537

[Current Perspective on Voltage-gated Potassium Channel Complex Antibody Associated Diseases].

PubMed

Watanabe, Osamu

2018-04-01

Voltage-gated potassium channel (VGKC) complex auto-antibodies were initially identified in Isaacs' syndrome (IS), which is characterized by muscle cramps and neuromyotonia. These antibodies were subsequently identified in patients with Morvan's syndrome (MoS), which includes IS in conjunction with psychosis, insomnia, and dysautonomia. The antibodies have also been detected in a patient with limbic encephalopathy (LE) presenting with prominent amnesia and frequent seizures. Typical cases of LE have adult-onset, with frequent, brief dystonic seizures that predominantly affect the arms and ipsilateral face, and has recently been termed faciobrachial dystonic seizures. Autoantibodies against the extracellular domains of VGKC complex proteins, leucine-rich glioma-inactivated 1 (LGI1), and contactin-associated protein-2 (Caspr2), occur in patients with IS, MoS, and LE. However, routine testing has detected VGKC complex antibodies without LGI1 or Caspr2 reactivities (double-negative) in patients with other diseases, such as Creutzfeldt-Jakob disease and amyotrophic lateral sclerosis. Furthermore, double-negative VGKC complex antibodies are often directed against cytosolic epitopes of Kv1 subunits. Therefore, these antibodies should no longer be classified as neuronal-surface antibodies and lacking pathogenic potential. Novel information has been generated regarding autoantibody disruption of the physiological functions of target proteins. LGI1 antibodies neutralize the interaction between LGI1 and ADAM22, thereby reducing the synaptic AMPA receptors. It may be that the main action is on inhibitory neurons, explaining why the loss of AMPA receptors causes amnesia, neuronal excitability and seizures.

Exploring physical and chemical factors influencing the properties of recombinant prion protein and the real-time quaking-induced conversion (RT-QuIC) assay.

PubMed

Cheng, Keding; Sloan, Angela; Avery, Kristen M; Coulthart, Michael; Carpenter, Michael; Knox, J David

2014-01-01

Real-time quaking-induced conversion (RT-QuIC), a highly specific and sensitive assay able to detect low levels of the disease-inducing isoform of the prion protein (PrP(d)) in brain tissue biopsies and cerebral spinal fluid, has great potential to become a method for diagnosing prion disease ante mortem. In order to standardize the assay method for routine analysis, an understanding of how physical and chemical factors affect the stability of the recombinant prion protein (rPrP) substrate and the RT-QuIC assay's sensitivity, specificity, and reproducibility is required. In this study, using sporadic Creutzfeldt-Jakob Disease brain homogenate to seed the reactions and an in vitro-expressed recombinant prion protein, hamster rPrP, as the substrate, the following factors affecting the RT-QuIC assay were examined: salt and substrate concentrations, substrate storage, and pH. Results demonstrated that both the generation of the quality and quantities of rPrP substrate critical to the reaction, as well as the RT-QuIC reaction itself required strict adherence to specific physical and chemical conditions. Once optimized, the RT-QuIC assay was confirmed to be a very specific and sensitive assay method for sCJD detection. Findings in this study indicate that further optimization and standardization of RT-QuIC assay is required before it can be adopted as a routine diagnostic test.

Olfactory Receptors in Non-Chemosensory Organs: The Nervous System in Health and Disease.

PubMed

Ferrer, Isidro; Garcia-Esparcia, Paula; Carmona, Margarita; Carro, Eva; Aronica, Eleonora; Kovacs, Gabor G; Grison, Alice; Gustincich, Stefano

2016-01-01

Olfactory receptors (ORs) and down-stream functional signaling molecules adenylyl cyclase 3 (AC3), olfactory G protein α subunit (Gαolf), OR transporters receptor transporter proteins 1 and 2 (RTP1 and RTP2), receptor expression enhancing protein 1 (REEP1), and UDP-glucuronosyltransferases (UGTs) are expressed in neurons of the human and murine central nervous system (CNS). In vitro studies have shown that these receptors react to external stimuli and therefore are equipped to be functional. However, ORs are not directly related to the detection of odors. Several molecules delivered from the blood, cerebrospinal fluid, neighboring local neurons and glial cells, distant cells through the extracellular space, and the cells' own self-regulating internal homeostasis can be postulated as possible ligands. Moreover, a single neuron outside the olfactory epithelium expresses more than one receptor, and the mechanism of transcriptional regulation may be different in olfactory epithelia and brain neurons. OR gene expression is altered in several neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2 with disease-, region- and subtype-specific patterns. Altered gene expression is also observed in the prefrontal cortex in schizophrenia with a major but not total influence of chlorpromazine treatment. Preliminary parallel observations have also shown the presence of taste receptors (TASRs), mainly of the bitter taste family, in the mammalian brain, whose function is not related to taste. TASRs in brain are also abnormally regulated in neurodegenerative diseases. These seminal observations point to the need for further studies on ORs and TASRs chemoreceptors in the mammalian brain.

Olfactory Receptors in Non-Chemosensory Organs: The Nervous System in Health and Disease

PubMed Central

Ferrer, Isidro; Garcia-Esparcia, Paula; Carmona, Margarita; Carro, Eva; Aronica, Eleonora; Kovacs, Gabor G.; Grison, Alice; Gustincich, Stefano

2016-01-01

Olfactory receptors (ORs) and down-stream functional signaling molecules adenylyl cyclase 3 (AC3), olfactory G protein α subunit (Gαolf), OR transporters receptor transporter proteins 1 and 2 (RTP1 and RTP2), receptor expression enhancing protein 1 (REEP1), and UDP-glucuronosyltransferases (UGTs) are expressed in neurons of the human and murine central nervous system (CNS). In vitro studies have shown that these receptors react to external stimuli and therefore are equipped to be functional. However, ORs are not directly related to the detection of odors. Several molecules delivered from the blood, cerebrospinal fluid, neighboring local neurons and glial cells, distant cells through the extracellular space, and the cells’ own self-regulating internal homeostasis can be postulated as possible ligands. Moreover, a single neuron outside the olfactory epithelium expresses more than one receptor, and the mechanism of transcriptional regulation may be different in olfactory epithelia and brain neurons. OR gene expression is altered in several neurodegenerative diseases including Parkinson’s disease (PD), Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) and sporadic Creutzfeldt-Jakob disease (sCJD) subtypes MM1 and VV2 with disease-, region- and subtype-specific patterns. Altered gene expression is also observed in the prefrontal cortex in schizophrenia with a major but not total influence of chlorpromazine treatment. Preliminary parallel observations have also shown the presence of taste receptors (TASRs), mainly of the bitter taste family, in the mammalian brain, whose function is not related to taste. TASRs in brain are also abnormally regulated in neurodegenerative diseases. These seminal observations point to the need for further studies on ORs and TASRs chemoreceptors in the mammalian brain. PMID:27458372

Risk perception of the "mad cow disease" in France: determinants and consequences.

PubMed

Setbon, Michel; Raude, Jocelyn; Fischler, Claude; Flahault, Antoine

2005-08-01

Since 1996, when bovine spongiform encephalopathy (BSE) was assessed as a possible human transmissible disease, a variant of Creutzfeldt-Jakob disease (vCJD), French people have entered into a long period of fear and avoidance of beef and bovine byproducts, which produced an unprecedented collapse in the beef market. This article deals with the perceived risk of the "mad cow disease" (MCD) in the French general population. Two surveys were conducted on a representative sample of the adult population, the first one in 2000 during the peak of the crisis and the second one 13 months later in a quieter period. The main assumption we made was that changes in beef consumption are strongly related to the perceived risk of MCD, which we defined as people's cognitive and affective responses to hazard. Our objective was to identify the determinants and consequences of this perceived risk and to compare them in different sociopolitical contexts. The results issued from a bivariate and multivariate analysis show that: (i) the distribution of most of the variables significantly related to the perceived risk identified in the first survey had changed in the second survey, in relation with the reduction of worry and the resumption of national beef consumption; (ii) the propensity for self-protection through avoiding or ceasing beef eating was more related to feelings of worry than to subjective vCJD risk assessments; and (iii) the main determinant of less avoidance to beef products was the preference for beef, a feeling identified prior to emergence of the risk of MCD, remaining unchanged in various contexts.

Recombinant human prion protein fragment 90-231, a useful model to study prion neurotoxicity.

PubMed

Corsaro, Alessandro; Thellung, Stefano; Villa, Valentina; Nizzari, Mario; Aceto, Antonio; Florio, Tullio

2012-01-01

Transmissible spongiform encephalopathies (TSE), or prion diseases, are a group of fatal neurodegenerative disorders of animals and humans. Human diseases include Creutzfeldt-Jakob (CJD) and Gerstmann-Straussler-Scheinker (GSSD) diseases, fatal familial insomnia, and Kuru. Human and animal TSEs share a common histopathology with a pathognomonic triad: spongiform vacuolation of the grey matter, neuronal death, glial proliferation, and, more inconstantly, amyloid deposition. According to the "protein only" hypothesis, TSEs are caused by a unique post-translational conversion of normal, host-encoded, protease-sensitive prion protein (PrP(sen) or PrP(C)) to an abnormal disease-associated isoform (PrP(res) or PrP(Sc)). To investigate the molecular mechanism of neurotoxicity induced by PrP(Sc) we developed a protocol to obtain millimolar amounts of soluble recombinant polypeptide encompassing the amino acid sequence 90-231 of human PrP (hPrP90-231). This protein corresponds to the protease-resistant prion protein fragment that originates after amino-terminal truncation. Importantly, hPrP90-231 has a flexible backbone that, similar to PrP(C), can undergo to structural rearrangement. This peptide, structurally resembling PrP(C), can be converted in a PrP(Sc)-like conformation, and thus represents a valuable model to study prion neurotoxicity. In this article we summarized our experimental evidence on the molecular and structural mechanisms responsible of hPrP90-231 neurotoxicity on neuroectodermal cell line SHSY5Y and the effects of some PrP pathogen mutations identified in familial TSE.

Syndromes of Rapidly Progressive Cognitive Decline-Our Experience

PubMed Central

Chandra, Sadanandavalli Retnaswami; Viswanathan, Lakshminarayanapuram Gopal; Pai, Anupama Ramakanth; Wahatule, Rahul; Alladi, Suvarna

2017-01-01

Background: Dementias are fairly slowly progressive degenerative diseases of brain for which treatment options are very less and carry a lot of burden on family and society. A small percentage of them are rapidly progressive and mostly carry a different course outcome. However, there are no definite criteria other than the time line for these patients. Aims: The aim of this was to identify and categorize the causes and course of rapidly progressive dementias seen in our center. Settings and Design: Patients who presented with rapid deterioration of cognitive functions within weeks to 1 year between 2011 and December 2016 were evaluated. Patients and Methods: All patients underwent all mandatory tests for dementia including brain imaging. Complete vasculitis workup, autoimmune encephalitis profile including Voltage Gated Potassium Channel, N-methyl-D-aspartic acid receptor, glutamic acid-decarboxylase, thyroid-peroxidase antibody, cerebrospinal fluid, and other special tests such as duodenal biopsy and paraneoplastic workup were done based on clinical indications. Results and Conclusions: Out of 144 patients 42 had immune-mediated encephalopathy, 18 had Creutzfeldt-Jakob disease, 3 had Vitamin B12 deficiency, 63 had infection with neurocysticercosis, 7 had tuberculosis, 2 had HIV, 1 had herpes simplex encephalitis, 1 had neurosyphilis, 1 Whipples disease, 1 had Subacute Sclerosing Panencephalitis, 1 had Mass lesion, 3 had Frontotemporal dementia, and 3 had small vessel disease. Good majority of these patients have infective and immune-mediated causes and less number belong to degenerative group. Therefore, caution is needed to look for treatable cause as it carries a different treatment options and outcome. PMID:28936074

Brain Iron Homeostasis: From Molecular Mechanisms To Clinical Significance and Therapeutic Opportunities

PubMed Central

Haldar, Swati; Tripathi, Ajai K.; Horback, Katharine; Wong, Joseph; Sharma, Deepak; Beserra, Amber; Suda, Srinivas; Anbalagan, Charumathi; Dev, Som; Mukhopadhyay, Chinmay K.; Singh, Ajay

2014-01-01

Abstract Iron has emerged as a significant cause of neurotoxicity in several neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), sporadic Creutzfeldt-Jakob disease (sCJD), and others. In some cases, the underlying cause of iron mis-metabolism is known, while in others, our understanding is, at best, incomplete. Recent evidence implicating key proteins involved in the pathogenesis of AD, PD, and sCJD in cellular iron metabolism suggests that imbalance of brain iron homeostasis associated with these disorders is a direct consequence of disease pathogenesis. A complete understanding of the molecular events leading to this phenotype is lacking partly because of the complex regulation of iron homeostasis within the brain. Since systemic organs and the brain share several iron regulatory mechanisms and iron-modulating proteins, dysfunction of a specific pathway or selective absence of iron-modulating protein(s) in systemic organs has provided important insights into the maintenance of iron homeostasis within the brain. Here, we review recent information on the regulation of iron uptake and utilization in systemic organs and within the complex environment of the brain, with particular emphasis on the underlying mechanisms leading to brain iron mis-metabolism in specific neurodegenerative conditions. Mouse models that have been instrumental in understanding systemic and brain disorders associated with iron mis-metabolism are also described, followed by current therapeutic strategies which are aimed at restoring brain iron homeostasis in different neurodegenerative conditions. We conclude by highlighting important gaps in our understanding of brain iron metabolism and mis-metabolism, particularly in the context of neurodegenerative disorders. Antioxid. Redox Signal. 20, 1324–1363. PMID:23815406

Brain iron homeostasis: from molecular mechanisms to clinical significance and therapeutic opportunities.

PubMed

Singh, Neena; Haldar, Swati; Tripathi, Ajai K; Horback, Katharine; Wong, Joseph; Sharma, Deepak; Beserra, Amber; Suda, Srinivas; Anbalagan, Charumathi; Dev, Som; Mukhopadhyay, Chinmay K; Singh, Ajay

2014-03-10

Iron has emerged as a significant cause of neurotoxicity in several neurodegenerative conditions, including Alzheimer's disease (AD), Parkinson's disease (PD), sporadic Creutzfeldt-Jakob disease (sCJD), and others. In some cases, the underlying cause of iron mis-metabolism is known, while in others, our understanding is, at best, incomplete. Recent evidence implicating key proteins involved in the pathogenesis of AD, PD, and sCJD in cellular iron metabolism suggests that imbalance of brain iron homeostasis associated with these disorders is a direct consequence of disease pathogenesis. A complete understanding of the molecular events leading to this phenotype is lacking partly because of the complex regulation of iron homeostasis within the brain. Since systemic organs and the brain share several iron regulatory mechanisms and iron-modulating proteins, dysfunction of a specific pathway or selective absence of iron-modulating protein(s) in systemic organs has provided important insights into the maintenance of iron homeostasis within the brain. Here, we review recent information on the regulation of iron uptake and utilization in systemic organs and within the complex environment of the brain, with particular emphasis on the underlying mechanisms leading to brain iron mis-metabolism in specific neurodegenerative conditions. Mouse models that have been instrumental in understanding systemic and brain disorders associated with iron mis-metabolism are also described, followed by current therapeutic strategies which are aimed at restoring brain iron homeostasis in different neurodegenerative conditions. We conclude by highlighting important gaps in our understanding of brain iron metabolism and mis-metabolism, particularly in the context of neurodegenerative disorders.

Resistance of Bovine Spongiform Encephalopathy (BSE) Prions to Inactivation

PubMed Central

Giles, Kurt; Glidden, David V.; Beckwith, Robyn; Seoanes, Rose; Peretz, David; DeArmond, Stephen J.; Prusiner, Stanley B.

2008-01-01

Distinct prion strains often exhibit different incubation periods and patterns of neuropathological lesions. Strain characteristics are generally retained upon intraspecies transmission, but may change on transmission to another species. We investigated the inactivation of two related prions strains: BSE prions from cattle and mouse-passaged BSE prions, termed 301V. Inactivation was manipulated by exposure to sodium dodecyl sulfate (SDS), variations in pH, and different temperatures. Infectivity was measured using transgenic mouse lines that are highly susceptible to either BSE or 301V prions. Bioassays demonstrated that BSE prions are up to 1,000-fold more resistant to inactivation than 301V prions while Western immunoblotting showed that short acidic SDS treatments reduced protease-resistant PrPSc from BSE prions and 301V prions at similar rates. Our findings argue that despite being derived from BSE prions, mouse 301V prions are not necessarily a reliable model for cattle BSE prions. Extending these comparisons to human sporadic Creutzfeldt-Jakob disease and hamster Sc237 prions, we found that BSE prions were 10- and 106-fold more resistant to inactivation, respectively. Our studies contend that any prion inactivation procedures must be validated by bioassay against the prion strain for which they are intended to be used. PMID:19008948

The prion-ZIP connection: From cousins to partners in iron uptake

PubMed Central

Singh, Neena; Asthana, Abhishek; Baksi, Shounak; Desai, Vilok; Haldar, Swati; Hari, Sahi; Tripathi, Ajai K

2015-01-01

ABSTRACT Converging observations from disparate lines of inquiry are beginning to clarify the cause of brain iron dyshomeostasis in sporadic Creutzfeldt-Jakob disease (sCJD), a neurodegenerative condition associated with the conversion of prion protein (PrPC), a plasma membrane glycoprotein, from α-helical to a β-sheet rich PrP-scrapie (PrPSc) isoform. Biochemical evidence indicates that PrPC facilitates cellular iron uptake by functioning as a membrane-bound ferrireductase (FR), an activity necessary for the transport of iron across biological membranes through metal transporters. An entirely different experimental approach reveals an evolutionary link between PrPC and the Zrt, Irt-like protein (ZIP) family, a group of proteins involved in the transport of zinc, iron, and manganese across the plasma membrane. Close physical proximity of PrPC with certain members of the ZIP family on the plasma membrane and increased uptake of extracellular iron by cells that co-express PrPC and ZIP14 suggest that PrPC functions as a FR partner for certain members of this family. The connection between PrPC and ZIP proteins therefore extends beyond common ancestry to that of functional cooperation. Here, we summarize evidence supporting the facilitative role of PrPC in cellular iron uptake, and implications of this activity on iron metabolism in sCJD brains. PMID:26689487

No Major Change in vCJD Agent Strain after Secondary Transmission via Blood Transfusion

PubMed Central

Bishop, Matthew T.; Ritchie, Diane L.; Will, Robert G.; Ironside, James W.; Head, Mark W.; Thomson, Val; Bruce, Moira; Manson, Jean C.

2008-01-01

Background The identification of transmission of variant Creutzfeldt-Jakob disease (vCJD) by blood transfusion has prompted investigation to establish whether there has been any alteration in the vCJD agent following this route of secondary transmission. Any increase in virulence or host adaptation would require a reassessment of the risk analyses relating to the possibility of a significant secondary outbreak of vCJD. Since there are likely to be carriers of the vCJD agent in the general population, there is a potential for further infection by routes such as blood transfusion or contaminated surgical instruments. Methodology We inoculated both wild-type and transgenic mice with material from the first case of transfusion associated vCJD infection. Principal Findings The strain transmission properties of blood transfusion associated vCJD infection show remarkable similarities to the strain of vCJD associated with transmission from bovine spongiform encephalopathy (BSE). Conclusions Although it has been hypothesized that adaptation of the BSE agent through secondary passage in humans may result in a greater risk of onward transmission due to an increased virulence of the agent for humans, our data presented here in two murine models suggest no significant alterations to transmission efficiency of the agent following human-to-human transmission of vCJD. PMID:18682737

Mechanisms of triggering H1 helix in prion proteins unfolding revealed by molecular dynamic simulation

NASA Astrophysics Data System (ADS)

Tseng, Chih-Yuan; Lee, H. C.

2006-03-01

In template-assistance model, normal Prion protein (PrP^C), the pathogen to cause several prion diseases such as Creutzfeldt-Jakob (CJD) in human, Bovine Spongiform Encephalopathy (BSE) in cow, and scrapie in sheep, converts to infectious prion (PrP^Sc) through a transient interaction with PrP^Sc. Furthermore, conventional studies showed S1-H1-S2 region in PrP^C to be the template of S1-S2 β-sheet in PrP^Sc, and Prion protein's conformational conversion may involve an unfolding of H1 and refolding into β-sheet. Here we prepare several mouse prion peptides that contain S1-H1-S2 region with specific different structures, which are corresponding to specific interactions, to investigate possible mechanisms to trigger H1 α-helix unfolding process via molecular dynamic simulation. Three properties, conformational transition, salt-bridge in H1, and hydrophobic solvent accessible surface (SAS) are analyzed. From these studies, we found the interaction that triggers H1 unfolding to be the one that causes dihedral angle at residue Asn^143 changes. Whereas interactions that cause S1 segment's conformational changes play a minor in this process. These studies offers an additional evidence for template-assistance model.

[Autoimmune Associated Encephalitis and Dementia].

PubMed

Watanabe, Osamu

2016-04-01

Antibodies against various neural surface antigens induce cognitive impairments. Anti-VGKC (voltage gated potassium channel) complex antibodies are well known as one of the causative autoantibodies. An anti-VGKC antibody was identified as the autoantibody in acquired neuromyotonia (Isaacs' syndrome), which causes muscle cramps and difficulty in opening the palm of the hands. However, this antibody also tests positive in autoimmune limbic encephalitis, which has a subacute progress and causes poor memory or epilepsy attacks. Typical cases have a distinctive adult-onset, frequent, brief dystonic seizure semiology that predominantly affects the arms and ipsilateral face. It has now been termed faciobrachial dystonic seizures. In recent years, the true target antigens of the anti-VGKC antibody of this VGKC limbic encephalitis have been recognized as leucine rich glioma inactivated protein (LGI)-1 and others. These antibodies to amnesia-related LGI-1 in limbic encephalitis neutralize the LGI-1-ADAM22 (an anchor protein) interaction and reduce synaptic AMPA receptors. There have been reports of limbic encephalitis associated with anti-VGKC complex antibodies mimicking Creutzfeldt-Jakob disease (CJD). Less than 2% of the patients with sporadic CJD (sCJD) develop serum anti-VGKC complex antibodies and, when positive, only at low titres. Low titres of these antibodies occur only rarely in suspected patients with sCJD, and when present, should be interpreted with caution.

Shadoo/PrP (Sprn0/0/Prnp0/0) double knockout mice

PubMed Central

Daude, Nathalie; Westaway, David

2012-01-01

Shadoo (Sho) is a brain glycoprotein with similarities to the unstructured region of PrPC. Frameshift alleles of the Sho gene, Sprn, are reported in variant Creutzfeldt-Jakob disease (vCJD) patients while Sprn mRNA knockdown in PrP-null (Prnp0/0) embryos produces lethality, advancing Sho as the hypothetical PrP-like “pi” protein. Also, Sho levels are reduced as misfolded PrP accumulates during prion infections. To penetrate these issues we created Sprn null alleles (Daude et al., Proc. Natl. Acad. Sci USA 2012; 109(23): 9035–40). Results from the challenge of Sprn null and TgSprn transgenic mice with rodent-adapted prions coalesce to define downregulation of Sho as a “tracer” for the formation of misfolded PrP. However, classical BSE and rodent-adapted BSE isolates may behave differently, as they do for other facets of the pathogenic process, and this intriguing variation warrants closer scrutiny. With regards to physiological function, double knockout mice (Sprn0/0/Prnp0/0) mice survived to over 600 d of age. This suggests that Sho is not pi, or, given the accumulating data for many activities for PrPC, that the pi hypothesis invoking a discrete signaling pathway to maintain neuronal viability is no longer tenable. PMID:22929230

Evaluation of the validity and reliability of A-scan ultrasound biometry with a single use disposable cover.

PubMed

Cass, K; Thompson, C M; Tromans, C; Wood, I C J

2002-03-01

The UK Medical Devices Agency has suggested that ophthalmic practitioners should, where practicable and not compromising clinical outcome, restrict corneal contact devices to single patient use to minimise a remote theoretical risk of transmission of new variant Creutzfeldt-Jakob disease (vCJD). This study reports on a modified technique of ultrasound A-scan biometry that complies with the MDA recommendations. The right eyes of 37 consecutive hospital patients had a series of biometry readings taken with a Humphrey 820 A-scan instrument with a plane wave transducer use d conventionally and with the addition of a disposable latex cover. Intrasessional repeatability of axial length measurements was similar for conventional readings--mean difference 0.027 mm, 95% confidence intervals (CI) +/- 0.44 mm and those taken with a disposable cover (0.028 mm, CI +/- 0.38). Intersessional repeatability was equivalent with (0.002 mm, CI +.- 0.51) and without a cover (0.03 mm, CI +/- 0.51). Readings with a cover were not significantly different from those without (paired t test; p >0.05), but tended to be greater (mean difference 0.085 mm, CI +/- 0.60). These findings suggest that corneal contact biometry with a disposable cover is a viable and theoretically safer alternative to the conventional technique.

Major food safety episodes in Taiwan: implications for the necessity of international collaboration on safety assessment and management.

PubMed

Li, Jih-Heng; Yu, Wen-Jing; Lai, Yuan-Hui; Ko, Ying-Chin

2012-07-01

The major food safety episodes that occurred in Taiwan during the past decade are briefly reviewed in this paper. Among the nine major episodes surveyed, with the exception of a U.S. beef (associated with Creutzfeldt-Jakob disease)-related incident, all the others were associated with chemical toxicants. The general public, which has a layperson attitude of zero tolerance toward food safety, may panic over these food-safety-associated incidents. However, the health effects and impacts of most incidents, with the exception of the melamine incident, were essentially not fully evaluated. The mass media play an important role in determining whether a food safety concern becomes a major incident. A well-coordinated and harmonized system for domestic and international collaboration to set up standards and regulations is critical, as observed in the incidents of pork with ractopamine, Chinese hairy crab with nitrofuran antibiotics, and U.S. wheat with malathion. In the future, it can be anticipated that food safety issues will draw more attention from the general public. For unknown new toxicants or illicit adulteration of food, the establishment of a more proactive safety assessment system to monitor potential threats and provide real-time information exchange is imperative. Copyright © 2012. Published by Elsevier B.V.

Insights into the Management of Emerging Infections: Regulating Variant Creutzfeldt-Jakob Disease Transfusion Risk in the UK and the US

PubMed Central

Ponte, Maya L

2006-01-01

Background Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease caused by infection with the agent of bovine spongiform encephalopathy. After the recognition of vCJD in the UK in 1996, many nations implemented policies intended to reduce the hypothetical risk of transfusion transmission of vCJD. This was despite the fact that no cases of transfusion transmission had yet been identified. In December 2003, however, the first case of vCJD in a recipient of blood from a vCJD-infected donor was announced. The aim of this study is to ascertain and compare the factors that influenced the motivation for and the design of regulations to prevent transfusion transmission of vCJD in the UK and US prior to the recognition of this case. Methods and Findings A document search was conducted to identify US and UK governmental policy statements and guidance, transcripts (or minutes when transcripts were not available) of scientific advisory committee meetings, research articles, and editorials published in medical and scientific journals on the topic of vCJD and blood transfusion transmission between March 1996 and December 2003. In addition, 40 interviews were conducted with individuals familiar with the decision-making process and/or the science involved. All documents and transcripts were coded and analyzed according to the methods and principles of grounded theory. Data showed that while resulting policies were based on the available science, social and historical factors played a major role in the motivation for and the design of regulations to protect against transfusion transmission of vCJD. First, recent experience with and collective guilt resulting from the transfusion-transmitted epidemics of HIV/AIDS in both countries served as a major, historically specific impetus for such policies. This history was brought to bear both by hemophilia activists and those charged with regulating blood products in the US and UK. Second, local specificities, such as the recall of blood products for possible vCJD contamination in the UK, contributed to a greater sense of urgency and a speedier implementation of regulations in that country. Third, while the results of scientific studies played a prominent role in the construction of regulations in both nations, this role was shaped by existing social and professional networks. In the UK, early focus on a European study implicating B-lymphocytes as the carrier of prion infectivity in blood led to the introduction of a policy that requires universal leukoreduction of blood components. In the US, early focus on an American study highlighting the ability of plasma to serve as a reservoir of prion infectivity led the FDA and its advisory panel to eschew similar measures. Conclusions The results of this study yield three important theoretical insights that pertain to the global management of emerging infectious diseases. First, because the perception and management of disease may be shaped by previous experience with disease, especially catastrophic experience, there is always the possibility for over-management of some possible routes of transmission and relative neglect of others. Second, local specificities within a given nation may influence the temporality of decision making, which in turn may influence the choice of disease management policies. Third, a preference for science-based risk management among nations will not necessarily lead to homogeneous policies. This is because the exposure to and interpretation of scientific results depends on the existing social and professional networks within a given nation. Together, these theoretical insights provide a framework for analyzing and anticipating potential conflicts in the international management of emerging infectious diseases. In addition, this study illustrates the utility of qualitative methods in investigating research questions that are difficult to assess through quantitative means. PMID:17076547

Insights into the management of emerging infections: regulating variant Creutzfeldt-Jakob disease transfusion risk in the UK and the US.

PubMed

Ponte, Maya L

2006-10-01

Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease caused by infection with the agent of bovine spongiform encephalopathy. After the recognition of vCJD in the UK in 1996, many nations implemented policies intended to reduce the hypothetical risk of transfusion transmission of vCJD. This was despite the fact that no cases of transfusion transmission had yet been identified. In December 2003, however, the first case of vCJD in a recipient of blood from a vCJD-infected donor was announced. The aim of this study is to ascertain and compare the factors that influenced the motivation for and the design of regulations to prevent transfusion transmission of vCJD in the UK and US prior to the recognition of this case. A document search was conducted to identify US and UK governmental policy statements and guidance, transcripts (or minutes when transcripts were not available) of scientific advisory committee meetings, research articles, and editorials published in medical and scientific journals on the topic of vCJD and blood transfusion transmission between March 1996 and December 2003. In addition, 40 interviews were conducted with individuals familiar with the decision-making process and/or the science involved. All documents and transcripts were coded and analyzed according to the methods and principles of grounded theory. Data showed that while resulting policies were based on the available science, social and historical factors played a major role in the motivation for and the design of regulations to protect against transfusion transmission of vCJD. First, recent experience with and collective guilt resulting from the transfusion-transmitted epidemics of HIV/AIDS in both countries served as a major, historically specific impetus for such policies. This history was brought to bear both by hemophilia activists and those charged with regulating blood products in the US and UK. Second, local specificities, such as the recall of blood products for possible vCJD contamination in the UK, contributed to a greater sense of urgency and a speedier implementation of regulations in that country. Third, while the results of scientific studies played a prominent role in the construction of regulations in both nations, this role was shaped by existing social and professional networks. In the UK, early focus on a European study implicating B-lymphocytes as the carrier of prion infectivity in blood led to the introduction of a policy that requires universal leukoreduction of blood components. In the US, early focus on an American study highlighting the ability of plasma to serve as a reservoir of prion infectivity led the FDA and its advisory panel to eschew similar measures. The results of this study yield three important theoretical insights that pertain to the global management of emerging infectious diseases. First, because the perception and management of disease may be shaped by previous experience with disease, especially catastrophic experience, there is always the possibility for over-management of some possible routes of transmission and relative neglect of others. Second, local specificities within a given nation may influence the temporality of decision making, which in turn may influence the choice of disease management policies. Third, a preference for science-based risk management among nations will not necessarily lead to homogeneous policies. This is because the exposure to and interpretation of scientific results depends on the existing social and professional networks within a given nation. Together, these theoretical insights provide a framework for analyzing and anticipating potential conflicts in the international management of emerging infectious diseases. In addition, this study illustrates the utility of qualitative methods in investigating research questions that are difficult to assess through quantitative means.

Ascertainment bias causes false signal of anticipation in genetic prion disease.

PubMed

Minikel, Eric Vallabh; Zerr, Inga; Collins, Steven J; Ponto, Claudia; Boyd, Alison; Klug, Genevieve; Karch, André; Kenny, Joanna; Collinge, John; Takada, Leonel T; Forner, Sven; Fong, Jamie C; Mead, Simon; Geschwind, Michael D

2014-10-02

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. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Diagnostic and prognostic value of human prion detection in cerebrospinal fluid.

PubMed

Foutz, Aaron; Appleby, Brian S; Hamlin, Clive; Liu, Xiaoqin; Yang, Sheng; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Fausett, Cameron; Wang, Han; Gambetti, Pierluigi; Zhang, Shulin; Hughson, Andrew; Tatsuoka, Curtis; Schonberger, Lawrence B; Cohen, Mark L; Caughey, Byron; Safar, Jiri G

2017-01-01

Several prion amplification systems have been proposed for detection of prions in cerebrospinal fluid (CSF), most recently, the measurements of prion seeding activity with second-generation real-time quaking-induced conversion (RT-QuIC). The objective of this study was to investigate the diagnostic performance of the RT-QuIC prion test in the broad phenotypic spectrum of prion diseases. We performed CSF RT-QuIC testing in 2,141 patients who had rapidly progressive neurological disorders, determined diagnostic sensitivity and specificity in 272 cases that were autopsied, and evaluated the impact of mutations and polymorphisms in the PRNP gene, and type 1 or type 2 human prions on diagnostic performance. The 98.5% diagnostic specificity and 92% sensitivity of CSF RT-QuIC in a blinded retrospective analysis matched the 100% specificity and 95% sensitivity of a blind prospective study. The CSF RT-QuIC differentiated 94% of cases of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 from the sCJD MM2 phenotype, and 80% of sCJD VV2 from sCJD VV1. The mixed prion type 1-2 and cases heterozygous for codon 129 generated intermediate CSF RT-QuIC patterns, whereas genetic prion diseases revealed distinct profiles for each PRNP gene mutation. The diagnostic performance of the improved CSF RT-QuIC is superior to surrogate marker tests for prion diseases such as 14-3-3 and tau proteins, and together with PRNP gene sequencing the test allows the major prion subtypes to be differentiated in vivo. This differentiation facilitates prediction of the clinicopathological phenotype and duration of the disease-two important considerations for envisioned therapeutic interventions. ANN NEUROL 2017;81:79-92. © 2016 American Neurological Association.

Unique properties of the classical bovine spongiform encephalopathy strain and its emergence from H-type bovine spongiform encephalopathy substantiated by VM transmission studies.

PubMed

Bencsik, Anna; Leboidre, Mikael; Debeer, Sabine; Aufauvre, Claire; Baron, Thierry

2013-03-01

In addition to classical bovine spongiform encephalopathy (C-BSE), which is recognized as being at the origin of the human variant form of Creutzfeldt-Jakob disease, 2 rare phenotypes of BSE (H-type BSE [H-BSE] and L-type BSE [L-BSE]) were identified in 2004. H-type BSE and L-BSE are considered to be sporadic forms of prion disease in cattle because they differ from C-BSE with respect to incubation period, vacuolar pathology in the brain, and biochemical properties of the protease-resistant prion protein (PrP) in natural hosts and in some mouse models that have been tested. Recently, we showed that H-BSE transmitted to C57Bl/6 mice resulted in a dissociation of the phenotypic features, that is, some mice showed an H-BSE phenotype, whereas others had a C-BSE phenotype. Here, these 2 phenotypes were further studied in VM mice and compared with cattle C-BSE, H-BSE, and L-BSE. Serial passages from the C-BSE-like phenotype on VM mice retained similarities with C-BSE. Moreover, our results indicate that strains 301V and 301C derived from C-BSE transmitted to VM and C57Bl/6 mice, respectively, are fundamentally the same strain. These VM transmission studies confirm the unique properties of the C-BSE strain and support the emergence of a strain that resembles C-BSE from H-BSE.

Experimental sheep BSE prions generate the vCJD phenotype when serially passaged in transgenic mice expressing human prion protein.

PubMed

Joiner, Susan; Asante, Emmanuel A; Linehan, Jacqueline M; Brock, Lara; Brandner, Sebastian; Bellworthy, Susan J; Simmons, Marion M; Hope, James; Collinge, John; Wadsworth, Jonathan D F

2018-03-15

The epizootic prion disease of cattle, bovine spongiform encephalopathy (BSE), causes variant Creutzfeldt-Jakob disease (vCJD) in humans following dietary exposure. While it is assumed that all cases of vCJD attributed to a dietary aetiology are related to cattle BSE, sheep and goats are susceptible to experimental oral challenge with cattle BSE prions and farmed animals in the UK were undoubtedly exposed to BSE-contaminated meat and bone meal during the late 1980s and early 1990s. Although no natural field cases of sheep BSE have been identified, it cannot be excluded that some BSE-infected sheep might have entered the European human food chain. Evaluation of the zoonotic potential of sheep BSE prions has been addressed by examining the transmission properties of experimental brain isolates in transgenic mice that express human prion protein, however to-date there have been relatively few studies. Here we report that serial passage of experimental sheep BSE prions in transgenic mice expressing human prion protein with methionine at residue 129 produces the vCJD phenotype that mirrors that seen when the same mice are challenged with vCJD prions from patient brain. These findings are congruent with those reported previously by another laboratory, and thereby strongly reinforce the view that sheep BSE prions could have acted as a causal agent of vCJD within Europe. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Nerve Growth Factor Increases mRNA Levels for the Prion Protein and the β -amyloid Protein Precursor in Developing Hamster Brain

NASA Astrophysics Data System (ADS)

Mobley, William C.; Neve, Rachael L.; Prusiner, Stanley B.; McKinley, Michael P.

1988-12-01

Deposition of amyloid filaments serves as a pathologic hallmark for some neurodegenerative disorders. The prion protein (PrP) is found in amyloid of animals with scrapie and humans with Creutzfeldt-Jakob disease; the β protein is present in amyloid deposits in Alzheimer disease and Down syndrome patients. These two proteins are derived from precursors that in the brain are expressed primarily in neurons and are membrane bound. We found that gene expression for PrP and the β -protein precursor (β -PP) is regulated in developing hamster brain. Specific brain regions showed distinct patterns of ontogenesis for PrP and β -PP mRNAs. The increases in PrP and β -PP mRNAs in developing basal forebrain coincided with an increase in choline acetyltransferase activity, raising the possibility that these markers might be coordinately controlled in cholinergic neurons and regulated by nerve growth factor (NGF). Injections of NGF into the brains of neonatal hamsters increased both PrP and β -PP mRNA levels. Increased PrP and β -PP mRNA levels induced by NGF were confined to regions that contain NGF-responsive cholinergic neurons and were accompanied by elevations in choline acetyltransferase. It remains to be established whether or not exogenous NGF acts to increase PrP and β -PP gene expression selectively in forebrain cholinergic neurons in the developing hamster and endogenous NGF regulates expression of these genes.

Phenotypic variability in familial prion diseases due to the D178N mutation

PubMed Central

Zarranz, J; Digon, A; Atares, B; Rodriguez-Martine..., A; Arce, A; Carrera, N; Fernandez-Manchol..., I; Fernandez-Martine..., M; Fernandez-Maizteg..., C; Forcadas, I; Galdos, L; Gomez-Esteban, J; Ibanez, A; Lezcano, E; d Lopez; Marti-Masso, J; Mendibe, M; Urtasun, M; Uterga, J; Saracibar, N; Velasco, F; de Pancorbo, M M

2005-01-01

Background: Between January 1993 and December 2003, 19 patients with familial prion diseases due to the D178N mutation were referred to the regional epidemiological registry for spongiform encephalopathies in the Basque Country in Spain, a small community of some 2 100 000 inhabitants. Methods: Ten further patients belonging to the same pedigrees were retrospectively ascertained through neurological or neuropathological records. In four of the patients, the diagnosis was confirmed by analysing DNA obtained from paraffin blocks. In this article, we report on the clinical, genetic, and pathological features of the 23 patients carrying the D178N mutation confirmed by genetic molecular analysis. Haplotyping studies suggest a founder effect among Basque born families, explaining in part this unusually high incidence of the D178N mutation in a small community. Only two patients (8%) lack familial antecedents. Results: We have observed a phenotypic variability even among homozygous 129MM patients. Our findings challenge the currently accepted belief that MM homozygosity in codon 129 is always related to a fatal familial insomnia (FFI) phenotype. Indeed, seven out of 17 patients with a 129MM genotype in this series presented with a Creutzfeldt-Jakob disease (CJD) clinicopathological picture. Conclusions: The considerable clinical and pathological overlapping observed among homozygous 129MM patients favours the view that FFI and CJD178 are the extremes of a spectrum rather than two discrete and separate entities. Other genetic or environmental factors apart from the polymorphism in codon 129 may play a role in determining the phenotypic expression of the D178N mutation in the PRNP gene. PMID:16227536

Prion protein gene analysis in three kindreds with fatal familial insomnia (FFI): Codon 178 mutation and codon 129 polymorphism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Medori, R.; Tritschler, H.J.

1993-10-01

Fatal familial insomnia (FFI) is a disease linked to a GAC(Asp) [yields] AAC(Asn) mutation in codon 178 of the prion protein (PrP) gene. FFI is characterized clinically by untreatable progressive insomnia, dysautonomia, and motor dysfunctions and is characterized pathologically by selective thalamic atrophy. The authors confirmed the 178[sup Asn] mutation in the PrP gene of a third FFI family of French ancestry. Three family members who are under 40 years of age and who inherited the mutation showed only reduced perfusion in the basal ganglia on single photon emission computerized tomography. Some FFI features differ from the clinical and neuropathologicmore » findings associated with 178[sup Asn] reported elsewhere. However, additional intragenic mutations accounting for the phenotypic differences were not observed in two affected individuals. In other sporadic and familial forms of Creutzfeldt-Jakob disease and Gerstmann-Straeussler syndrome, Met or Val homozygosity at polymorphic codon 129 is associated with a more severe phenotype, younger age at onset, and faster progression. In FFI, young and old individuals at disease onset had 129[sup Met/Val]. Moreover, of five 178[sup Asn] individuals who are above age-at-onset range and who are well, two have 129[sup Met] and three have 129[sup Met/Val], suggesting that polymorphic site 129 does not modulate FFI phenotypic expression. Genetic heterogeneity and environment may play an important role in inter- and intrafamilial variability of the 178[sup Asn] mutation. 32 refs., 5 figs., 1 tab.« less

Are Major Dementias Triggered by Poor Blood Flow to the Brain? Theoretical Considerations.

PubMed

de la Torre, Jack C

2017-01-01

There is growing evidence that chronic brain hypoperfusion plays a central role in the development of Alzheimer's disease (AD) long before dyscognitive symptoms or amyloid-β accumulation in the brain appear. This commentary proposes that dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and Creutzfeldt-Jakob disease (CJD) may also develop from chronic brain hypoperfusion following a similar but not identical neurometabolic breakdown as AD. The argument to support this conclusion is that chronic brain hypoperfusion, which is found at the early stages of the three dementias reviewed here, will reduce oxygen delivery and lower oxidative phosphorylation promoting a steady decline in the synthesis of the cell energy fuel adenosine triphosphate (ATP). This process is known to lead to oxidative stress. Virtually all neurodegenerative diseases, including FTD, DLB, and CJD, are characterized by oxidative stress that promotes inclusion bodies which differ in structure, location, and origin, as well as which neurological disorder they typify. Inclusion bodies have one thing in common; they are known to diminish autophagic activity, the protective intracellular degradative process that removes malformed proteins, protein aggregates, and damaged subcellular organelles that can disrupt neuronal homeostasis. Neurons are dependent on autophagy for their normal function and survival. When autophagic activity is diminished or impaired in neurons, high levels of unfolded or misfolded proteins overwhelm and downregulate the neuroprotective activity of unfolded protein response which is unable to get rid of dysfunctional organelles such as damaged mitochondria and malformed proteins at the synapse. The endpoint of this neuropathologic process results in damaged synapses, impaired neurotransmission, cognitive decline, and dementia.

Evidence that bank vole PrP is a universal acceptor for prions.

PubMed

Watts, Joel C; Giles, Kurt; Patel, Smita; Oehler, Abby; DeArmond, Stephen J; Prusiner, Stanley B

2014-04-01

Bank voles are uniquely susceptible to a wide range of prion strains isolated from many different species. To determine if this enhanced susceptibility to interspecies prion transmission is encoded within the sequence of the bank vole prion protein (BVPrP), we inoculated Tg(M109) and Tg(I109) mice, which express BVPrP containing either methionine or isoleucine at polymorphic codon 109, with 16 prion isolates from 8 different species: humans, cattle, elk, sheep, guinea pigs, hamsters, mice, and meadow voles. Efficient disease transmission was observed in both Tg(M109) and Tg(I109) mice. For instance, inoculation of the most common human prion strain, sporadic Creutzfeldt-Jakob disease (sCJD) subtype MM1, into Tg(M109) mice gave incubation periods of ∼200 days that were shortened slightly on second passage. Chronic wasting disease prions exhibited an incubation time of ∼250 days, which shortened to ∼150 days upon second passage in Tg(M109) mice. Unexpectedly, bovine spongiform encephalopathy and variant CJD prions caused rapid neurological dysfunction in Tg(M109) mice upon second passage, with incubation periods of 64 and 40 days, respectively. Despite the rapid incubation periods, other strain-specified properties of many prion isolates--including the size of proteinase K-resistant PrPSc, the pattern of cerebral PrPSc deposition, and the conformational stability--were remarkably conserved upon serial passage in Tg(M109) mice. Our results demonstrate that expression of BVPrP is sufficient to engender enhanced susceptibility to a diverse range of prion isolates, suggesting that BVPrP may be a universal acceptor for prions.

Human prion diseases: surgical lessons learned from iatrogenic prion transmission.

PubMed

Bonda, David J; Manjila, Sunil; Mehndiratta, Prachi; Khan, Fahd; Miller, Benjamin R; Onwuzulike, Kaine; Puoti, Gianfranco; Cohen, Mark L; Schonberger, Lawrence B; Cali, Ignazio

2016-07-01

The human prion diseases, or transmissible spongiform encephalopathies, have captivated our imaginations since their discovery in the Fore linguistic group in Papua New Guinea in the 1950s. The mysterious and poorly understood "infectious protein" has become somewhat of a household name in many regions across the globe. From bovine spongiform encephalopathy (BSE), commonly identified as mad cow disease, to endocannibalism, media outlets have capitalized on these devastatingly fatal neurological conditions. Interestingly, since their discovery, there have been more than 492 incidents of iatrogenic transmission of prion diseases, largely resulting from prion-contaminated growth hormone and dura mater grafts. Although fewer than 9 cases of probable iatrogenic neurosurgical cases of Creutzfeldt-Jakob disease (CJD) have been reported worldwide, the likelihood of some missed cases and the potential for prion transmission by neurosurgery create considerable concern. Laboratory studies indicate that standard decontamination and sterilization procedures may be insufficient to completely remove infectivity from prion-contaminated instruments. In this unfortunate event, the instruments may transmit the prion disease to others. Much caution therefore should be taken in the absence of strong evidence against the presence of a prion disease in a neurosurgical patient. While the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) have devised risk assessment and decontamination protocols for the prevention of iatrogenic transmission of the prion diseases, incidents of possible exposure to prions have unfortunately occurred in the United States. In this article, the authors outline the historical discoveries that led from kuru to the identification and isolation of the pathological prion proteins in addition to providing a brief description of human prion diseases and iatrogenic forms of CJD, a brief history of prion disease nosocomial transmission, and a summary of the CDC and WHO guidelines for prevention of prion disease transmission and decontamination of prion-contaminated neurosurgical instruments.

Human prion diseases: surgical lessons learned from iatrogenic prion transmission

PubMed Central

Bonda, David J.; Manjila, Sunil; Mehndiratta, Prachi; Khan, Fahd; Miller, Benjamin R.; Onwuzulike, Kaine; Puoti, Gianfranco; Cohen, Mark L.; Schonberger, Lawrence B.; Cali, Ignazio

2016-01-01

The human prion diseases, or transmissible spongiform encephalopathies, have captivated our imaginations since their discovery in the Fore linguistic group in Papua New Guinea in the 1950s. The mysterious and poorly understood “infectious protein” has become somewhat of a household name in many regions across the globe. From bovine spongiform encephalopathy (BSE), commonly identified as mad cow disease, to endocannibalism, media outlets have capitalized on these devastatingly fatal neurological conditions. Interestingly, since their discovery, there have been more than 492 incidents of iatrogenic transmission of prion diseases, largely resulting from prion-contaminated growth hormone and dura mater grafts. Although fewer than 9 cases of probable iatrogenic neurosurgical cases of Creutzfeldt-Jakob disease (CJD) have been reported worldwide, the likelihood of some missed cases and the potential for prion transmission by neurosurgery create considerable concern. Laboratory studies indicate that standard decontamination and sterilization procedures may be insufficient to completely remove infectivity from prion-contaminated instruments. In this unfortunate event, the instruments may transmit the prion disease to others. Much caution therefore should be taken in the absence of strong evidence against the presence of a prion disease in a neurosurgical patient. While the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) have devised risk assessment and decontamination protocols for the prevention of iatrogenic transmission of the prion diseases, incidents of possible exposure to prions have unfortunately occurred in the United States. In this article, the authors outline the historical discoveries that led from kuru to the identification and isolation of the pathological prion proteins in addition to providing a brief description of human prion diseases and iatrogenic forms of CJD, a brief history of prion disease nosocomial transmission, and a summary of the CDC and WHO guidelines for prevention of prion disease transmission and decontamination of prion-contaminated neurosurgical instruments. PMID:27364252

Hsp31, a member of the DJ-1 superfamily, is a multitasking stress responder with chaperone activity

PubMed Central

Aslam, Kiran; Hazbun, Tony R.

2016-01-01

ABSTRACT Among different types of protein aggregation, amyloids are a biochemically well characterized state of protein aggregation that are associated with a large number of neurodegenerative diseases including Parkinson's disease, Alzheimer and Creutzfeldt-Jakob disease. Yeast, Saccharomyces cerevisiae is an insightful model to understand the underlying mechanism of protein aggregation. Many yeast molecular chaperones can modulate aggregation and misfolding of proteins including α-Syn and the Sup35 prion. Hsp31 is a homodimeric protein structurally similar to human DJ-1, a Parkinson's disease-linked protein, and both are members of the DJ-1/ThiJ/PfpI superfamily. An emerging view is that Hsp31 and its associated superfamily members each have divergent multitasking functions that have the common theme of responding and managing various types of cellular stress. Hsp31 has several biochemical activities including chaperone and detoxifying enzyme activities that modulate at various points of a stress pathway such as toxicity associated with protein misfolding. However, we have shown the protective role of Hsp31's chaperone activity can operate independent of detoxifying enzyme activities in preventing the early stages of protein aggregate formation and associated cellular toxicities. We provide additional data that collectively supports the multiple functional roles that can be accomplished independent of each other. We present data indicating Hsp31 purified from yeast is more active compared to expression and purification from E. coli suggesting that posttranslational modifications could be important for Hsp31 to be fully active. We also compare the similarities and differences in activities among paralogs of Hsp31 supporting a model in which this protein family has overlapping but diverging roles in responding to various sources of cellular stresses. PMID:27097320

Geographical BSE risk assessment and its impact on disease detection and dissemination.

PubMed

Salman, Mo; Silano, Vittorio; Heim, Dagmar; Kreysa, Joachim

2012-08-01

Bovine Spongiform Encephalopathy (BSE) rapidly evolved into an issue of major public concern particularly when, in 1996, evidence was provided that this disease had crossed the species barrier and infected humans in the UK with what has become known as "variant Creutzfeldt Jakob Disease" (vCJD). The aim of this paper is to describe the European Geographical BSE risk assessment (GBR) that was successfully used for assessing the qualitative likelihood that BSE could be present in a country where it was not yet officially recognized. It also discusses how this can lead to risk-based and therefore preventive management of BSE at national and international levels. The basic assumption of the GBR method is that the BSE agent is initially introduced into a country's domestic cattle production system through the importation of contaminated feedstuffs or live cattle. This is referred to as an "external challenge". The ability of the system to cope with such a challenge is, in turn, referred to as its "stability": a stable system will not allow the BSE agent to propagate and amplify following its introduction, while an unstable system will. The BSE-status of a country assessed by this system was used by the European Commission as the basis for trade legislation rules for cattle and their products. The GBR was an invaluable tool in evaluating the potential global spread of BSE as it demonstrated how a disease could be transferred through international trade. This was shown to be a critical factor to address in reducing the spread and amplification of BSE throughout the world. Furthermore, GBR resulted in the implementation of additional measures and management activities both to improve surveillance and to prevent transmission within the cattle population. Copyright © 2012 Elsevier B.V. All rights reserved.

Proteolysis suppresses spontaneous prion generation in yeast.

PubMed

Okamoto, Atsushi; Hosoda, Nao; Tanaka, Anri; Newnam, Gary P; Chernoff, Yury O; Hoshino, Shin-Ichi

2017-12-08

Prions are infectious proteins that cause fatal neurodegenerative disorders including Creutzfeldt-Jakob and bovine spongiform encephalopathy (mad cow) diseases. The yeast [ PSI + ] prion is formed by the translation-termination factor Sup35, is the best-studied prion, and provides a useful model system for studying such diseases. However, despite recent progress in the understanding of prion diseases, the cellular defense mechanism against prions has not been elucidated. Here, we report that proteolytic cleavage of Sup35 suppresses spontaneous de novo generation of the [ PSI + ] prion. We found that during yeast growth in glucose media, a maximum of 40% of Sup35 is cleaved at its N-terminal prion domain. This cleavage requires the vacuolar proteases PrA-PrB. Cleavage occurs in a manner dependent on translation but independently of autophagy between the glutamine/asparagine-rich (Q/N-rich) stretch critical for prion formation and the oligopeptide-repeat region required for prion maintenance, resulting in the removal of the Q/N-rich stretch from the Sup35 N terminus. The complete inhibition of Sup35 cleavage, by knocking out either PrA ( pep4 Δ) or PrB ( prb1 Δ), increased the rate of de novo formation of [ PSI + ] prion up to ∼5-fold, whereas the activation of Sup35 cleavage, by overproducing PrB, inhibited [ PSI + ] formation. On the other hand, activation of the PrB pathway neither cleaved the amyloid conformers of Sup35 in [ PSI + ] strains nor eliminated preexisting [ PSI + ]. These findings point to a mechanism antagonizing prion generation in yeast. Our results underscore the usefulness of the yeast [ PSI + ] prion as a model system to investigate defense mechanisms against prion diseases and other amyloidoses. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Diagnostic and Prognostic Value of Human Prion Detection in Cerebrospinal Fluid

PubMed Central

Foutz, Aaron; Appleby, Brian S.; Hamlin, Clive; Liu, Xiaoqin; Yang, Sheng; Cohen, Yvonne; Chen, Wei; Blevins, Janis; Fausett, Cameron; Wang, Han; Gambetti, Pierluigi; Zhang, Shulin; Hughson, Andrew; Tatsuoka, Curtis; Schonberger, Lawrence B.; Cohen, Mark L.; Caughey, Byron; Safar, Jiri G.

2016-01-01

Objective Several prion amplification systems have been proposed for detection of prions in cerebrospinal fluid (CSF), most recently, the measurements of prion seeding activity with second-generation real-time quaking-induced conversion (RT-QuIC). The objective of this study was to investigate the diagnostic performance of the RT-QuIC prion test in the broad phenotypic spectrum of prion diseases. Methods We performed CSF RT-QuIC testing in 2,141 patients who had rapidly progressive neurological disorders, determined diagnostic sensitivity and specificity in 272 cases which were autopsied, and evaluated the impact of mutations and polymorphisms in the PRNP gene, and Type 1 or Type 2 of human prions on diagnostic performance. Results The 98.5% diagnostic specificity and 92% sensitivity of CSF RT-QuIC in a blinded retrospective analysis matched the 100% specificity and 95% sensitivity of a blind prospective study. The CSF RT-QuIC differentiated 94% of cases of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 from the sCJD MM2 phenotype, and 80% of sCJD VV2 from sCJD VV1. The mixed prion type 1–2 and cases heterozygous for codon 129 generated intermediate CSF RT-QuIC patterns, while genetic prion diseases revealed distinct profiles for each PRNP gene mutation. Interpretation The diagnostic performance of the improved CSF RT-QuIC is superior to surrogate marker tests for prion diseases such as 14-3-3 and Tau proteins and together with PRNP gene sequencing, the test allows the major prion subtypes to be differentiated in vivo. This differentiation facilitates prediction of the clinicopathological phenotype and duration of the disease—two important considerations for envisioned therapeutic interventions. PMID:27893164

Drivers: A Biologically Contextualized, Cross-Inferential View of the Epidemiology of Neurodegenerative Disorders

PubMed Central

de Pedro-Cuesta, Jesús; Martínez-Martín, Pablo; Rábano, Alberto; Alcalde-Cabero, Enrique; José García López, Fernando; Almazán-Isla, Javier; Ruiz-Tovar, María; Medrano, Maria-José; Avellanal, Fuencisla; Calero, Olga; Calero, Miguel

2016-01-01

Background: Sutherland et al. (2011) suggested that, instead of risk factors for single neurodegenerative disorders (NDDs), there was a need to identify specific “drivers”, i.e., risk factors with impact on specific deposits, such as amyloid-β, tau, or α-synuclein, acting across entities. Objectives and Methods: Redefining drivers as “neither protein/gene- nor entity-specific features identifiable in the clinical and general epidemiology of conformational NDDs (CNDDs) as potential footprints of templating/spread/transfer mechanisms”, we conducted an analysis of the epidemiology of ten CNDDs, searching for patterns. Results: We identified seven potential drivers, each of which was shared by at least two CNDDs: 1) an age-at-exposure-related susceptibility to Creutzfeldt-Jakob disease (CJD) and several late-life CNDDs; 2) a relationship between age at onset, survival, and incidence; 3) shared genetic risk factors for CJD and late-life CNNDs; 4) partly shared personal (diagnostic, educational, behavioral, and social risk factors) predating clinical onset of late-life CNDDs; 5) two environmental risk factors, namely, surgery for sporadic CJD and amyotrophic lateral sclerosis, and Bordetella pertussis infection for Parkinson’s disease; 6) reticulo-endothelial system stressors or general drivers (andropause or premenopausal estrogen deficiency, APOEɛ4, and vascular risk factors) for late-life CNDDs such as dementia/Alzheimer’s disease, type-2 diabetes mellitus, and some sporadic cardiac and vascular degenerative diseases; and 7) a high, invariant incidence ratio of sporadic to genetic forms of mid- and late-life CNDDs, and type-2 diabetes mellitus. Conclusion: There might be a systematic epidemiologic pattern induced by specific proteins (PrP, TDP-43, SOD1, α-synuclein, amyloid-β, tau, Langerhans islet peptide, and transthyretin) or established combinations of these. PMID:26923014

A pilot to examine the logistical and feasibility issues in testing deceased tissue donors for vCJD using tonsil as the analyte.

PubMed

Warwick, Ruth M; Armitage, W John; Chandrasekar, Akila; Mallinson, Gary; Poniatowski, Stefan; Clarkson, Anthony

2012-03-01

Transplanted tissues have transmitted transmissible spongiform encephalopathies and in the UK there have been more cases of variant Creutzfeldt-Jakob disease (vCJD) than elsewhere in the world. A pilot study was undertaken to look at the feasibility of testing for vCJD in deceased donors using tonsillar tissue. This pilot showed that obtaining consent for removal and testing tonsil tissue was feasible. Donor eligibility for inclusion in the pilot was limited to tissue donors from the National Health Service Blood and Transplant, Tissue Services and to donors shared with the Corneal Transplant Service Eye Banks. Obtaining tonsillar tissue in the immediate post-mortem period was limited by the presence of rigor mortis. Tonsillar tissue was suitable for routine analysis for the presence of prion associated with vCJD in deceased tissue donors. Production and processing of tissue was straightforward and a low assay background was obtained from most samples. Since palatine and lingual tonsil tissue can be obtained in pairs it was possible, in the majority of cases, to set aside an intact sample for confirmatory testing if required. In one instance a sample was reactive by Western blot. However, the pattern of reactivity was not typical for that obtained from vCJD patients. Unfortunately the sample was not of sufficient quality for the confirmatory test to provide a conclusive result.

Quantification of thymosin beta(4) in human cerebrospinal fluid using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

PubMed

Urso, Elena; Le Pera, Maria; Bossio, Sabrina; Sprovieri, Teresa; Qualtieri, Antonio

2010-07-01

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) has been applied to the analysis of a wide range of biomolecules. To date, there are two specific areas of application where MALDI-TOF-MS is viewed as impractical: analysis of low-mass analytes and relative quantitative applications. However, these limitations can be overcome and quantification can be routine. Increased levels of thymosin beta(4) (TB4) have been recently found in cerebrospinal fluid (CSF) from Creutzfeldt-Jakob disease (CJD) patients. Our objective was to apply a label-free quantitative application of MALDI-TOF-MS to measure TB4 levels in human CSF by adding the oxidized form of TB4 as an internal standard. The relative peak area or peak height ratios of the native TB4 to the added oxidized form were evaluated. Considering the relative peak area ratios, healthy individuals showed a mean value of 40.8+/-21.27 ng/ml, whereas CJD patients showed high values with a mean of 154+/-59.07 ng/ml, in agreement with the previous observation found in CJD patients. Similar results were obtained considering peak height ratios. The proposed method may provide a simple and rapid screening method for quantification on CSF of TB4 levels suitable for diagnostic purposes. 2010 Elsevier Inc. All rights reserved.

Evidence for more cost-effective surveillance options for bovine spongiform encephalopathy (BSE) and scrapie in Great Britain.

PubMed

Wall, Ben A; Arnold, Mark E; Radia, Devi; Gilbert, Will; Ortiz-Pelaez, Angel; Stärk, Katharina Dc; Van Klink, Ed; Guitian, Javier

2017-08-10

Transmissible spongiform encephalopathies (TSEs) are an important public health concern. Since the emergence of bovine spongiform encephalopathy (BSE) during the 1980s and its link with human Creutzfeldt-Jakob disease, active surveillance has been a key element of the European Union's TSE control strategy. Success of this strategy means that now, very few cases are detected compared with the number of animals tested. Refining surveillance strategies would enable resources to be redirected towards other public health priorities. Cost-effectiveness analysis was performed on several alternative strategies involving reducing the number of animals tested for BSE and scrapie in Great Britain and, for scrapie, varying the ratio of sheep sampled in the abattoir to fallen stock (which died on the farm). The most cost-effective strategy modelled for BSE involved reducing the proportion of fallen stock tested from 100% to 75%, producing a cost saving of ca GBP 700,000 per annum. If 50% of fallen stock were tested, a saving of ca GBP 1.4 million per annum could be achieved. However, these reductions are predicted to increase the period before surveillance can detect an outbreak. For scrapie, reducing the proportion of abattoir samples was the most cost-effective strategy modelled, with limited impact on surveillance effectiveness. This article is copyright of The Authors, 2017.

The Structural Architecture of an Infectious Mammalian Prion Using Electron Cryomicroscopy.

PubMed

Vázquez-Fernández, Ester; Vos, Matthijn R; Afanasyev, Pavel; Cebey, Lino; Sevillano, Alejandro M; Vidal, Enric; Rosa, Isaac; Renault, Ludovic; Ramos, Adriana; Peters, Peter J; Fernández, José Jesús; van Heel, Marin; Young, Howard S; Requena, Jesús R; Wille, Holger

2016-09-01

The structure of the infectious prion protein (PrPSc), which is responsible for Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy, has escaped all attempts at elucidation due to its insolubility and propensity to aggregate. PrPSc replicates by converting the non-infectious, cellular prion protein (PrPC) into the misfolded, infectious conformer through an unknown mechanism. PrPSc and its N-terminally truncated variant, PrP 27-30, aggregate into amorphous aggregates, 2D crystals, and amyloid fibrils. The structure of these infectious conformers is essential to understanding prion replication and the development of structure-based therapeutic interventions. Here we used the repetitive organization inherent to GPI-anchorless PrP 27-30 amyloid fibrils to analyze their structure via electron cryomicroscopy. Fourier-transform analyses of averaged fibril segments indicate a repeating unit of 19.1 Å. 3D reconstructions of these fibrils revealed two distinct protofilaments, and, together with a molecular volume of 18,990 Å3, predicted the height of each PrP 27-30 molecule as ~17.7 Å. Together, the data indicate a four-rung β-solenoid structure as a key feature for the architecture of infectious mammalian prions. Furthermore, they allow to formulate a molecular mechanism for the replication of prions. Knowledge of the prion structure will provide important insights into the self-propagation mechanisms of protein misfolding.

Assessment of prion reduction filters in decreasing infectivity of ultracentrifuged 263K scrapie-infected brain homogenates in "spiked" human blood and red blood cells.

PubMed

Cardone, Franco; Sowemimo-Coker, Samuel; Abdel-Haq, Hanin; Sbriccoli, Marco; Graziano, Silvia; Valanzano, Angelina; Berardi, Vito Angelo; Galeno, Roberta; Puopolo, Maria; Pocchiari, Maurizio

2014-04-01

The safety of red blood cells (RBCs) is of concern because of the occurrence of four transfusion-transmitted variant Creutzfeldt-Jakob disease (vCJD) cases in the United Kingdom. The absence of validated screening tests requires the use of procedures to remove prions from blood to minimize the risk of transmission. These procedures must be validated using infectious prions in a form that is as close as possible to one in blood. Units of human whole blood (WB) and RBCs were spiked with high-speed supernatants of 263K scrapie-infected hamster brain homogenates. Spiked samples were leukoreduced and then passed through prion-removing filters (Pall Corporation). In another experiment, RBCs from 263K scrapie-infected hamsters were treated as above, and residual infectivity was measured by bioassay. The overall removal of infectivity by the filters from prion-spiked WB and RBCs was approximately two orders of magnitude. No infectivity was detected in filtered hamster RBCs endogenously infected with scrapie. The use of prion-removing filters may help to reduce the risk of transfusion-transmitted vCJD. To avoid overestimation of prion removal efficiency in validation studies, it may be more appropriate to use supernates from ultracentrifugation of scrapie-infected hamster brain homogenate rather than the current standard brain homogenates. © 2013 American Association of Blood Banks.

Partial verification bias and incorporation bias affected accuracy estimates of diagnostic studies for biomarkers that were part of an existing composite gold standard.

PubMed

Karch, Annika; Koch, Armin; Zapf, Antonia; Zerr, Inga; Karch, André

2016-10-01

To investigate how choice of gold standard biases estimates of sensitivity and specificity in studies reassessing the diagnostic accuracy of biomarkers that are already part of a lifetime composite gold standard (CGS). We performed a simulation study based on the real-life example of the biomarker "protein 14-3-3" used for diagnosing Creutzfeldt-Jakob disease. Three different types of gold standard were compared: perfect gold standard "autopsy" (available in a small fraction only; prone to partial verification bias), lifetime CGS (including the biomarker under investigation; prone to incorporation bias), and "best available" gold standard (autopsy if available, otherwise CGS). Sensitivity was unbiased when comparing 14-3-3 with autopsy but overestimated when using CGS or "best available" gold standard. Specificity of 14-3-3 was underestimated in scenarios comparing 14-3-3 with autopsy (up to 24%). In contrast, overestimation (up to 20%) was observed for specificity compared with CGS; this could be reduced to 0-10% when using the "best available" gold standard. Choice of gold standard affects considerably estimates of diagnostic accuracy. Using the "best available" gold standard (autopsy where available, otherwise CGS) leads to valid estimates of specificity, whereas sensitivity is estimated best when tested against autopsy alone. Copyright © 2016 Elsevier Inc. All rights reserved.

Evaluation of the validity and reliability of A-scan ultrasound biometry with a single use disposable cover

PubMed Central

Cass, K; Thompson, C M; Tromans, C; Wood, I C J

2002-01-01

Background: The UK Medical Devices Agency has suggested that ophthalmic practitioners should, where practicable and not compromising clinical outcome, restrict corneal contact devices to single patient use to minimise a remote theoretical risk of transmission of new variant Creutzfeldt-Jakob disease (vCJD). This study reports on a modified technique of ultrasound A-scan biometry that complies with the MDA recommendations. Methods: The right eyes of 37 consecutive hospital patients had a series of biometry readings taken with a Humphrey 820 A-scan instrument with a plane wave transducer use d conventionally and with the addition of a disposable latex cover. Results: Intrasessional repeatability of axial length measurements was similar for conventional readings—mean difference 0.027 mm, 95% confidence intervals (CI) ± 0.44 mm and those taken with a disposable cover (0.028 mm, CI ± 0.38). Intersessional repeatability was equivalent with (0.002 mm, CI ± 0.51) and without a cover (0.03 mm, CI ± 0.51). Readings with a cover were not significantly different from those without (paired t test; p >0.05), but tended to be greater (mean difference 0.085 mm, CI ± 0.60). Conclusions: These findings suggest that corneal contact biometry with a disposable cover is a viable and theoretically safer alternative to the conventional technique. PMID:11864896

Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases.

PubMed

Kabir, M Enamul; Safar, Jiri G

2014-01-01

There is a growing body of evidence indicating that number of human neurodegenerative diseases, including Alzheimer disease, Parkinson disease, fronto-temporal dementias, and amyotrophic lateral sclerosis, propagate in the brain via prion-like intercellular induction of protein misfolding. Prions cause lethal neurodegenerative diseases in humans, the most prevalent being sporadic Creutzfeldt-Jakob disease (sCJD); they self-replicate and spread by converting the cellular form of prion protein (PrP(C)) to a misfolded pathogenic conformer (PrP(Sc)). The extensive phenotypic heterogeneity of human prion diseases is determined by polymorphisms in the prion protein gene, and by prion strain-specific conformation of PrP(Sc). Remarkably, even though informative nucleic acid is absent, prions may undergo rapid adaptation and evolution in cloned cells and upon crossing the species barrier. In the course of our investigation of this process, we isolated distinct populations of PrP(Sc) particles that frequently co-exist in sCJD. The human prion particles replicate independently and undergo competitive selection of those with lower initial conformational stability. Exposed to mutant substrate, the winning PrP(Sc) conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to the lowest stability. Thus, the evolution and adaptation of human prions is enabled by a dynamic collection of distinct populations of particles, whose evolution is governed by the selection of progressively less stable, faster replicating PrP(Sc) conformers. This fundamental biological mechanism may explain the drug resistance that some prions gained after exposure to compounds targeting PrP(Sc). Whether the phenotypic heterogeneity of other neurodegenerative diseases caused by protein misfolding is determined by the spectrum of misfolded conformers (strains) remains to be established. However, the prospect that these conformers may evolve and adapt by a prion-like mechanism calls for the reevaluation of therapeutic strategies that target aggregates of misfolded proteins, and argues for new therapeutic approaches that will focus on prior pathogenetic steps.

No added diagnostic value of non-phosphorylated tau fraction (p-taurel) in CSF as a biomarker for differential dementia diagnosis.

PubMed

Goossens, Joery; Bjerke, Maria; Struyfs, Hanne; Niemantsverdriet, Ellis; Somers, Charisse; Van den Bossche, Tobi; Van Mossevelde, Sara; De Vil, Bart; Sieben, Anne; Martin, Jean-Jacques; Cras, Patrick; Goeman, Johan; De Deyn, Peter Paul; Van Broeckhoven, Christine; van der Zee, Julie; Engelborghs, Sebastiaan

2017-07-14

The Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers Aβ 1-42 , t-tau, and p-tau 181 overlap with other diseases. New tau modifications or epitopes, such as the non-phosphorylated tau fraction (p-tau rel ), may improve differential dementia diagnosis. The goal of this study is to investigate if p-tau rel can improve the diagnostic performance of the AD CSF biomarker panel for differential dementia diagnosis. The study population consisted of 45 AD, 45 frontotemporal lobar degeneration (FTLD), 45 dementia with Lewy bodies (DLB), and 21 Creutzfeldt-Jakob disease (CJD) patients, and 20 cognitively healthy controls. A substantial subset of the patients was pathology-confirmed. CSF levels of Aβ 1-42 , t-tau, p-tau 181 , and p-tau rel were determined with commercially available single-analyte enzyme-linked immunosorbent assay (ELISA) kits. Diagnostic performance was evaluated by receiver operating characteristic (ROC) curve analyses, and area under the curve (AUC) values were compared using DeLong tests. The diagnostic performance of single markers as well as biomarker ratios was determined for each pairwise comparison of different dementia groups and controls. The addition of p-tau rel to the AD biomarker panel decreased its diagnostic performance when discriminating non-AD, FTLD, and DLB from AD. As a single marker, p-tau rel increased the diagnostic performance for CJD. No significant difference was found in AUC values with the addition of p-tau rel when differentiating between AD or non-AD dementias and controls. The addition of p-tau rel to the AD CSF biomarker panel failed to improve differentiation between AD and non-AD dementias.

Genetic compendium of 1511 human brains available through the UK Medical Research Council Brain Banks Network Resource.

PubMed

Keogh, Michael J; Wei, Wei; Wilson, Ian; Coxhead, Jon; Ryan, Sarah; Rollinson, Sara; Griffin, Helen; Kurzawa-Akanbi, Marzena; Santibanez-Koref, Mauro; Talbot, Kevin; Turner, Martin R; McKenzie, Chris-Anne; Troakes, Claire; Attems, Johannes; Smith, Colin; Al Sarraj, Safa; Morris, Chris M; Ansorge, Olaf; Pickering-Brown, Stuart; Ironside, James W; Chinnery, Patrick F

2017-01-01

Given the central role of genetic factors in the pathogenesis of common neurodegenerative disorders, it is critical that mechanistic studies in human tissue are interpreted in a genetically enlightened context. To address this, we performed exome sequencing and copy number variant analysis on 1511 frozen human brains with a diagnosis of Alzheimer's disease (AD, n = 289), frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS, n = 252), Creutzfeldt-Jakob disease (CJD, n = 239), Parkinson's disease (PD, n = 39), dementia with Lewy bodies (DLB, n = 58), other neurodegenerative, vascular, or neurogenetic disorders (n = 266), and controls with no significant neuropathology (n = 368). Genomic DNA was extracted from brain tissue in all cases before exome sequencing (Illumina Nextera 62 Mb capture) with variants called by FreeBayes; copy number variant (CNV) analysis (Illumina HumanOmniExpress-12 BeadChip); C9orf72 repeat expansion detection; and APOE genotyping. Established or likely pathogenic heterozygous, compound heterozygous, or homozygous variants, together with the C9orf72 hexanucleotide repeat expansions and a copy number gain of APP, were found in 61 brains. In addition to known risk alleles in 349 brains (23.9% of 1461 undergoing exome sequencing), we saw an association between rare variants in GRN and DLB. Rare CNVs were found in <1.5% of brains, including copy number gains of PRPH that were overrepresented in AD. Clinical, pathological, and genetic data are available, enabling the retrieval of specific frozen brains through the UK Medical Research Council Brain Banks Network. This allows direct access to pathological and control human brain tissue based on an individual's genetic architecture, thus enabling the functional validation of known genetic risk factors and potentially pathogenic alleles identified in future studies. © 2017 Keogh et al.; Published by Cold Spring Harbor Laboratory Press.

Scrg1 is induced in TSE and brain injuries, and associated with autophagy.

PubMed

Dron, Michel; Bailly, Yannick; Beringue, Vincent; Haeberlé, Anne-Marie; Griffond, Bernadette; Risold, Pierre-Yves; Tovey, Michael G; Laude, Hubert; Dandoy-Dron, Françoise

2005-07-01

We have previously identified Scrg1, a gene with increased cerebral mRNA levels in transmissible spongiform encephalopathies (TSE) such as scrapie, bovine spongiform encephalopathy and Creutzfeldt-Jakob disease. In this study, Scrg1-immunoreactive cells, essentially neurons, were shown to be widely distributed throughout the brain of scrapie-infected mice, while only rare and weakly immunoreactive cells could be detected in the brain of non-infected normal mice. Induction of the protein was confirmed by Western blot analysis. At the ultrastructural level, Scrg1 protein was associated with dictyosomes of the Golgi apparatus and autophagic vacuoles in the central neurons of the scrapie-infected mice. These results suggested a role for Scrg1 in the pathological changes observed in TSE. We have generated transgenic mice specifically expressing Scrg1 in neurons. No significant differences in the time course of the disease were detected between transgenic and non-transgenic mice infected with scrapie prions. However, tight association of Scrg1 with autophagic vacuoles was again observed in brain neurons of infected transgenic mice. High levels of the protein were also detected in degenerating Purkinje cells of Ngsk Prnp 0/0 mice overexpressing the Prnd gene coding for doppel, a neurotoxic paralogue of the prion protein. Furthermore, induction of Scrg1 protein was observed in the brain of mice injured by canine distemper virus or gold thioglucose treatment. Taken together, our results indicate that Scrg1 is associated with neurodegenerative processes in TSE, but is not directly linked to dysregulation of prion protein.

[PSI+] Prion transmission barriers protect Saccharomyces cerevisiae from infection: intraspecies 'species barriers'.

PubMed

Bateman, David A; Wickner, Reed B

2012-02-01

[PSI+] is a prion of Sup35p, an essential translation termination and mRNA turnover factor. The existence of lethal [PSI+] variants, the absence of [PSI+] in wild strains, the mRNA turnover function of the Sup35p prion domain, and the stress reaction to prion infection suggest that [PSI+] is a disease. Nonetheless, others have proposed that [PSI+] and other yeast prions benefit their hosts. We find that wild Saccharomyces cerevisiae strains are polymorphic for the sequence of the prion domain and particularly in the adjacent M domain. Here we establish that these variations within the species produce barriers to prion transmission. The barriers are partially asymmetric in some cases, and evidence for variant specificity in barriers is presented. We propose that, as the PrP 129M/V polymorphism protects people from Creutzfeldt-Jakob disease, the Sup35p polymorphisms were selected to protect yeast cells from prion infection. In one prion incompatibility group, the barrier is due to N109S in the Sup35 prion domain and several changes in the middle (M) domain, with either the single N109S mutation or the group of M changes (without the N109S) producing a barrier. In another, the barrier is due to a large deletion in the repeat domain. All are outside the region previously believed to determine transmission compatibility. [SWI+], a prion of the chromatin remodeling factor Swi1p, was also proposed to benefit its host. We find that none of 70 wild strains carry this prion, suggesting that it is not beneficial.

Whole Blood Gene Expression Profiling in Preclinical and Clinical Cattle Infected with Atypical Bovine Spongiform Encephalopathy

PubMed Central

Xerxa, Elena; Barbisin, Maura; Chieppa, Maria Novella; Krmac, Helena; Vallino Costassa, Elena; Vatta, Paolo; Simmons, Marion; Caramelli, Maria; Casalone, Cristina; Corona, Cristiano

2016-01-01

Prion diseases, such as bovine spongiform encephalopathies (BSE), are transmissible neurodegenerative disorders affecting humans and a wide variety of mammals. Variant Creutzfeldt-Jakob disease (vCJD), a prion disease in humans, has been linked to exposure to BSE prions. This classical BSE (cBSE) is now rapidly disappearing as a result of appropriate measures to control animal feeding. Besides cBSE, two atypical forms (named H- and L-type BSE) have recently been described in Europe, Japan, and North America. Here we describe the first wide-spectrum microarray analysis in whole blood of atypical BSE-infected cattle. Transcriptome changes in infected animals were analyzed prior to and after the onset of clinical signs. The microarray analysis revealed gene expression changes in blood prior to the appearance of the clinical signs and during the progression of the disease. A set of 32 differentially expressed genes was found to be in common between clinical and preclinical stages and showed a very similar expression pattern in the two phases. A 22-gene signature showed an oscillating pattern of expression, being differentially expressed in the preclinical stage and then going back to control levels in the symptomatic phase. One gene, SEL1L3, was downregulated during the progression of the disease. Most of the studies performed up to date utilized various tissues, which are not suitable for a rapid analysis of infected animals and patients. Our findings suggest the intriguing possibility to take advantage of whole blood RNA transcriptional profiling for the preclinical identification of prion infection. Further, this study highlighted several pathways, such as immune response and metabolism that may play an important role in peripheral prion pathogenesis. Finally, the gene expression changes identified in the present study may be further investigated as a fingerprint for monitoring the progression of disease and for developing targeted therapeutic interventions. PMID:27073865

Retinal function and morphology are altered in cattle infected with the prion disease transmissible mink encephalopathy.

PubMed

Smith, J D; Greenlee, J J; Hamir, A N; Richt, J A; Greenlee, M H West

2009-09-01

Transmissible spongiform encephalopathies (TSEs) are a group of diseases that result in progressive and invariably fatal neurologic disease in both animals and humans. TSEs are characterized by the accumulation of an abnormal protease-resistant form of the prion protein in the central nervous system. Transmission of infectious TSEs is believed to occur via ingestion of prion protein-contaminated material. This material is also involved in the transmission of bovine spongiform encephalopathy ("mad cow disease") to humans, which resulted in the variant form of Creutzfeldt-Jakob disease. Abnormal prion protein has been reported in the retina of TSE-affected cattle, but despite these observations, the specific effect of abnormal prion protein on retinal morphology and function has not been assessed. The objective of this study was to identify and characterize potential functional and morphologic abnormalities in the retinas of cattle infected with a bovine-adapted isolate of transmissible mink encephalopathy. We used electroretinography and immunohistochemistry to examine retinas from 10 noninoculated and 5 transmissible mink encephalopathy-inoculated adult Holstein steers. Here we show altered retinal function, as evidenced by prolonged implicit time of the electroretinogram b-wave, in transmissible mink encephalopathy-infected cattle before the onset of clinical illness. We also demonstrate disruption of rod bipolar cell synaptic terminals, indicated by decreased immunoreactivity for the alpha isoform of protein kinase C and vesicular glutamate transporter 1, and activation of Müller glia, as evidenced by increased glial fibrillary acidic protein and glutamine synthetase expression, in the retinas of these cattle at the time of euthanasia due to clinical deterioration. This is the first study to identify both functional and morphologic alterations in the retinas of TSE-infected cattle. Our results support future efforts to focus on the retina for the development of new strategies for the diagnosis of TSEs.

Generalized cerebral atrophy seen on MRI in a naturally exposed animal model for creutzfeldt-jakob disease

PubMed Central

2010-01-01

Background Magnetic resonance imaging has been used in the diagnosis of human prion diseases such as sCJD and vCJD, but patients are scanned only when clinical signs appear, often at the late stage of disease. This study attempts to answer the questions "Could MRI detect prion diseases before clinical symptoms appear?, and if so, with what confidence?" Methods Scrapie, the prion disease of sheep, was chosen for the study because sheep can fit into a human sized MRI scanner (and there were no large animal MRI scanners at the time of this study), and because the USDA had, at the time of the study, a sizeable sample of scrapie exposed sheep, which we were able to use for this purpose. 111 genetically susceptible sheep that were naturally exposed to scrapie were used in this study. Results Our MRI findings revealed no clear, consistent hyperintense or hypointense signal changes in the brain on either clinically affected or asymptomatic positive animals on any sequence. However, in all 37 PrPSc positive sheep (28 asymptomatic and 9 symptomatic), there was a greater ventricle to cerebrum area ratio on MRI compared to 74 PrPSc negative sheep from the scrapie exposed flock and 6 control sheep from certified scrapie free flocks as defined by immunohistochemistry (IHC). Conclusions Our findings indicate that MRI imaging can detect diffuse cerebral atrophy in asymptomatic and symptomatic sheep infected with scrapie. Nine of these 37 positive sheep, including 2 one-year old animals, were PrPSc positive only in lymph tissues but PrPSc negative in the brain. This suggests either 1) that the cerebral atrophy/neuronal loss is not directly related to the accumulation of PrPSc within the brain or 2) that the amount of PrPSc in the brain is below the detectable limits of the utilized immunohistochemistry assay. The significance of these findings remains to be confirmed in human subjects with CJD. PMID:21108848

Comparative Incidence of Conformational, Neurodegenerative Disorders

PubMed Central

de Pedro-Cuesta, Jesús; Rábano, Alberto; Martínez-Martín, Pablo; Ruiz-Tovar, María; Alcalde-Cabero, Enrique; Almazán-Isla, Javier; Avellanal, Fuencisla; Calero, Miguel

2015-01-01

Background The purpose of this study was to identify incidence and survival patterns in conformational neurodegenerative disorders (CNDDs). Methods We identified 2563 reports on the incidence of eight conditions representing sporadic, acquired and genetic, protein-associated, i.e., conformational, NDD groups and age-related macular degeneration (AMD). We selected 245 papers for full-text examination and application of quality criteria. Additionally, data-collection was completed with detailed information from British, Swedish, and Spanish registries on Creutzfeldt-Jakob disease (CJD) forms, amyotrophic lateral sclerosis (ALS), and sporadic rapidly progressing neurodegenerative dementia (sRPNDd). For each condition, age-specific incidence curves, age-adjusted figures, and reported or calculated median survival were plotted and examined. Findings Based on 51 valid reported and seven new incidence data sets, nine out of eleven conditions shared specific features. Age-adjusted incidence per million person-years increased from ≤1.5 for sRPNDd, different CJD forms and Huntington's disease (HD), to 1589 and 2589 for AMD and Alzheimer's disease (AD) respectively. Age-specific profiles varied from (a) symmetrical, inverted V-shaped curves for low incidences to (b) those increasing with age for late-life sporadic CNDDs and for sRPNDd, with (c) a suggested, intermediate, non-symmetrical inverted V-shape for fronto-temporal dementia and Parkinson's disease. Frequently, peak age-specific incidences from 20–24 to ≥90 years increased with age at onset and survival. Distinct patterns were seen: for HD, with a low incidence, levelling off at middle age, and long median survival, 20 years; and for sRPNDd which displayed the lowest incidence, increasing with age, and a short median disease duration. Interpretation These results call for a unified population view of NDDs, with an age-at-onset-related pattern for acquired and sporadic CNDDs. The pattern linking age at onset to incidence magnitude and survival might be explained by differential pathophysiological mechanisms associated with specific misfolded protein deposits. PMID:26335347

Survival of blood transfusion recipients identified by a look-back investigation.

PubMed

Dorsey, Kerri A; Moritz, Erin D; Notari, Edward P; Schonberger, Lawrence B; Dodd, Roger Y

2014-01-01

Survival of blood transfusion recipients is a critical consideration in assessing the outcomes of transfusion. Data from the USA on the short- and long-term survival of recipients are limited. Blood product recipients were identified through a look-back study of Creutzfeldt-Jakob disease. Survival data were obtained from searches of the National Death Index or the Social Security Death Master File. Short- and long-term survival of recipients was analysed through descriptive statistics, Kaplan-Meier survival analysis, and stratified Cox proportional hazard modelling. This study includes data from 575 blood product recipients. One half of the recipients died within the first year of transfusion and the median time to death was 1.1 years. Survival rates at 5, 10, 15, 20, and 25 years after transfusion were 32%, 22%, 15%, 12%, and 9%, respectively. Survival rates varied with age at transfusion and type of component received, but not by gender. Survival after transfusion varied by year of transfusion, with recipients transfused in 1980-1989 having longer post-transfusion survival than those transfused in 2000-2010 (p=0.049). In multivariate models, the type of component transfused, but not the year of transfusion, was a significant predictor of survival among recipients; this effect varied by age. We provide an estimate of survival time from a geographically diverse sample of blood product recipients in the USA. Predictors of post-transfusion survival are numerous and complex, and may include year of transfusion and type of component transfused.

Homogenous photocatalytic decontamination of prion infected stainless steel and titanium surfaces.

PubMed

Berberidou, Chrysanthi; Xanthopoulos, Konstantinos; Paspaltsis, Ioannis; Lourbopoulos, Athanasios; Polyzoidou, Eleni; Sklaviadis, Theodoros; Poulios, Ioannis

2013-01-01

Prions are notorious for their extraordinary resistance to traditional methods of decontamination, rendering their transmission a public health risk. Iatrogenic Creutzfeldt-Jakob disease (iCJD) via contaminated surgical instruments and medical devices has been verified both experimentally and clinically. Standard methods for prion inactivation by sodium hydroxide or sodium hypochlorite have failed, in some cases, to fully remove prion infectivity, while they are often impractical for routine applications. Prion accumulation in peripheral tissues and indications of human-to-human bloodborne prion transmission, highlight the need for novel, efficient, yet user-friendly methods of prion inactivation. Here we show both in vitro and in vivo that homogenous photocatalytic oxidation, mediated by the photo-Fenton reagent, has the potential to inactivate the pathological prion isoform adsorbed on metal substrates. Photocatalytic oxidation with 224 μg mL(-1) Fe (3+), 500 μg mL(-1) h(-1) H 2O 2, UV-A for 480 min lead to 100% survival in golden Syrian hamsters after intracranial implantation of stainless steel wires infected with the 263K prion strain. Interestingly, photocatalytic treatment of 263K infected titanium wires, under the same experimental conditions, prolonged the survival interval significantly, but failed to eliminate infectivity, a result that we correlate with the increased adsorption of PrP(Sc) on titanium, in comparison to stainless steel. Our findings strongly indicate that our, user--and environmentally--friendly protocol can be safely applied to the decontamination of prion infected stainless steel surfaces.

Meeting Report: 2015 PDA Virus & TSE Safety Forum.

PubMed

Willkommen, Hannelore; Blümel, Johannes; Brorson, Kurt; Chen, Dayue; Chen, Qi; Gröner, Albrecht; Kreil, Thomas R; Ruffing, Michel; Ruiz, Sol; Scott, Dorothy; Silvester, Glenda

2016-01-01

The report provides a summary of the presentations at the Virus & TSE Safety Forum 2015 organized by the Parenteral Drug Association (PDA) and held in Cascais, Portugal, from 9 to 11 June, 2015. As with previous conferences of this series, the PDA Virus & TSE Safety Forum 2015 provided an excellent forum for the exchange of information and opinions between the industry, research organizations, and regulatory bodies. Regulatory updates on virus and TSE safety aspects illustrating current topics of discussion at regulatory agencies in Europe and the United States were provided; the conference covered emerging viruses and new virus detection systems that may be used for the investigation of human pathogenic viruses as well as the virus safety of cell substrates and of raw material of ovine/caprine or human origin. Progress of development and use of next-generation sequencing methods was shown by several examples. Virus clearance data illustrating the effectiveness of inactivation or removal methods were presented and data provided giving insight into the mechanism of action of these technologies. In the transmissible spongiform encephalopathy (TSE) part of the conference, the epidemiology of variant Creutzfeldt-Jakob disease was reviewed and an overview about diagnostic tests provided; current thinking about the spread and propagation of prions was presented and the inactivation of prions by disinfection (equipment) and in production of bovine-derived reagents (heparin) shown. The current report provides an overview about the outcomes of the 2015 PDA Virus & TSE Safety Forum, a unique event in this field. © PDA, Inc. 2016.

Different 2-Aminothiazole Therapeutics Produce Distinct Patterns of Scrapie Prion Neuropathology in Mouse Brains.

PubMed

Giles, Kurt; Berry, David B; Condello, Carlo; Hawley, Ronald C; Gallardo-Godoy, Alejandra; Bryant, Clifford; Oehler, Abby; Elepano, Manuel; Bhardwaj, Sumita; Patel, Smita; Silber, B Michael; Guan, Shenheng; DeArmond, Stephen J; Renslo, Adam R; Prusiner, Stanley B

2015-10-01

Because no drug exists that halts or even slows any neurodegenerative disease, developing effective therapeutics for any prion disorder is urgent. We recently reported two compounds (IND24 and IND81) with the 2-aminothiazole (2-AMT) chemical scaffold that almost doubled the incubation times in scrapie prion-infected, wild-type (wt) FVB mice when given in a liquid diet. Remarkably, oral prophylactic treatment with IND24 beginning 14 days prior to intracerebral prion inoculation extended survival from ∼120 days to over 450 days. In addition to IND24, we evaluated the pharmacokinetics and efficacy of five additional 2-AMTs; one was not followed further because its brain penetration was poor. Of the remaining four new 2-AMTs, IND114338 doubled and IND125 tripled the incubation times of RML-inoculated wt and Tg4053 mice overexpressing wt mouse prion protein (PrP), respectively. Neuropathological examination of the brains from untreated controls showed a widespread deposition of self-propagating, β-sheet-rich "scrapie" isoform (PrP(Sc)) prions accompanied by a profound astrocytic gliosis. In contrast, mice treated with 2-AMTs had lower levels of PrP(Sc) and associated astrocytic gliosis, with each compound resulting in a distinct pattern of deposition. Notably, IND125 prevented both PrP(Sc) accumulation and astrocytic gliosis in the cerebrum. Progressive central nervous system dysfunction in the IND125-treated mice was presumably due to the PrP(Sc) that accumulated in their brainstems. Disappointingly, none of the four new 2-AMTs prolonged the lives of mice expressing a chimeric human/mouse PrP transgene inoculated with Creutzfeldt-Jakob disease prions. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

[Hashimoto's encephalopathy and autoantibodies].

PubMed

Yoneda, Makoto

2013-04-01

Encephalopathy occasionally occurs in association with thyroid disorders, but most of these are treatable. These encephalopathies include a neuropsychiatric disorder associated with hypothyroidism, called myxedema encephalopathy. Moreover, Hashimoto's encephalopathy (HE) has been recognized as a new clinical disease based on an autoimmune mechanism associated with Hashimoto's thyroiditis. Steroid treatment was successfully administered to these patients. Recently, we discovered that the serum autoantibodies against the NH2-terminal of α-enolase (NAE) are highly specific diagnostic biomarkers for HE. Further, we analyzed serum anti-NAE autoantibodies and the clinical features in many cases of HE from institutions throughout Japan and other countries. Approximately half of assessed HE patients carry anti-NAE antibodies. The age was widely distributed with 2 peaks (20-30 years and 50-70 years). Most HE patients were in euthyroid states, and all patients had anti-thyroid (TG) antibodies and anti-thyroid peroxidase (TPO) antibodies. Anti-TSH receptor (TSH-R) antibodies were observed in some cases. The common neuropsychiatry features are consciousness disturbance and psychosis, followed by cognitive dysfunction, involuntary movements, seizures, and ataxia. Abnormalities on electroencephalography (EEG) and decreased cerebral blood flow on brain SPECT were common findings, whereas abnormal findings on brain magnetic resonance imaging (MRI) were rare. HE patients have various clinical phenotypes such as the acute encephalopathy form, the chronic psychiatric form, and other particular clinical forms, including limbic encephalitis, progressive cerebellar ataxia, and Creutzfeldt-Jakob disease (CJD)-like form. The cerebellar ataxic form of HE clinically mimics spinocerebellar degeneration (SCD) and is characterized by the absence of nystagmus, absent or mild cerebellar atrophy, and lazy background activities on EEG. Taken together, these data suggest that the possibility of encephalopathy associated with thyroid disorders must be considered.

Differentiation of sCJD and vCJD forms by automated analysis of basal ganglia intensity distribution in multisequence MRI of the brain--definition and evaluation of new MRI-based ratios.

PubMed

Linguraru, Marius George; Ayache, Nicholas; Bardinet, Eric; Ballester, Miguel Angel González; Galanaud, Damien; Haïk, Stéphane; Faucheux, Baptiste; Hauw, Jean-Jacques; Cozzone, Patrick; Dormont, Didier; Brandel, Jean-Philippe

2006-08-01

We present a method for the analysis of basal ganglia (including the thalamus) for accurate detection of human spongiform encephalopathy in multisequence magnetic resonance imaging (MRI) of the brain. One common feature of most forms of prion protein diseases is the appearance of hyperintensities in the deep grey matter area of the brain in T2-weighted magnetic resonance (MR) images. We employ T1, T2, and Flair-T2 MR sequences for the detection of intensity deviations in the internal nuclei. First, the MR data are registered to a probabilistic atlas and normalized in intensity. Then smoothing is applied with edge enhancement. The segmentation of hyperintensities is performed using a model of the human visual system. For more accurate results, a priori anatomical data from a segmented atlas are employed to refine the registration and remove false positives. The results are robust over the patient data and in accordance with the clinical ground truth. Our method further allows the quantification of intensity distributions in basal ganglia. The caudate nuclei are highlighted as main areas of diagnosis of sporadic Creutzfeldt-Jakob Disease (sCJD), in agreement with the histological data. The algorithm permitted the classification of the intensities of abnormal signals in sCJD patient FLAIR images with a higher hypersignal in caudate nuclei (10/10) and putamen (6/10) than in thalami. Defining normalized MRI measures of the intensity relations between the internal grey nuclei of patients, we robustly differentiate sCJD and variant CJD (vCJD) patients, in an attempt to create an automatic classification tool of human spongiform encephalopathies.

Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series

PubMed Central

Webb, T. E. F.; Poulter, M.; Beck, J.; Uphill, J.; Adamson, G.; Campbell, T.; Linehan, J.; Powell, C.; Brandner, S.; Pal, S.; Siddique, D.; Wadsworth, J. D.; Joiner, S.; Alner, K.; Petersen, C.; Hampson, S.; Rhymes, C.; Treacy, C.; Storey, E.; Geschwind, M. D.; Nemeth, A. H.; Wroe, S.; Mead, S.

2008-01-01

The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers. PMID:18757886

Neurocognitive features distinguishing primary central nervous system lymphoma from other possible causes of rapidly progressive dementia.

PubMed

Deutsch, Mariel B; Mendez, Mario F

2015-03-01

Define the neurocognitive features of primary central nervous system lymphoma (PCNSL) presenting with dementia, and compare with other causes of rapidly progressive dementia (RPD). PCNSL can present as an RPD. Differentiating PCNSL from other RPDs is critical because lymphomatous dementia may be reversible, and untreated PCNSL is fatal. We performed a meta-analysis of case reports of dementia from PCNSL (between 1950 and 2013); 20 patients (14 with lymphomatosis cerebri) met our criteria. We compared these patients to a case series of patients with RPD from Creutzfeldt-Jakob disease and other non-PCNSL etiologies (Sala et al, 2012. Alzheimer Dis Assoc Disord. 26:267-271). Median age was 66 years (range 41 to 81); 70% were men. Time from symptom onset to evaluation was <6 months in 65%. No patients had seizures; 5% had headaches; 45% had non-aphasic speech difficulty. There was significantly more memory impairment in patients with PCNSL than other RPDs and significantly less myoclonus and parkinsonism. Behavioral changes and cerebellar signs were not significantly different. Significantly more patients with PCNSL than other RPDs had white matter changes; significantly fewer had atrophy. Elevated CSF protein and pleocytosis were more frequent in PCNSL; patients with other RPDs tended to have normal CSF±14-3-3 protein. Unlike patients with RPD from other causes, those with PCNSL commonly present with impaired memory, apathy, and abnormal speech and gait, without headache, seizure, or myoclonus. White matter changes and CSF abnormalities predominate. Improved clinical awareness of PCNSL can prompt earlier diagnosis and treatment.

The role of the donor liaison officer at PlusLife (Perth Bone and Tissue Bank Inc.), Western Australia.

PubMed

Smythe, Claire; White, Nicola; Winter, Joyleen; Cowie, Anne

2015-06-01

Femoral head donation at the time of hip replacement surgery provides a much needed resource of bone allograft to orthopaedic surgeons. Prior to 2005, potential femoral head donors were identified and consented in the hospital setting on the day of surgery. This resulted in over 40 % of donations failing post operatively suggesting that more effort could be given to pre-operative screening resulting in substantial savings in the cost associated with collection and testing of donors who were subsequently failed. The Donor Liaison role was implemented in 2005 to coordinate a Femoral Head Donation program maximising the number of successful donations through pre-operative screening. This study reviews the effectiveness of pre-operative screening of potential femoral head donors at PlusLife from 2002-2012. A retrospective audit of the database was undertaken 2002-2012 and medical/social reasons for pre-operative and postoperative failures were collated into 4 main categories to enable comparison: malignancy, autoimmune conditions, variant Creutzfeldt Jakob disease risk and general medical/social reasons. The number of femoral heads failed post operatively has decreased significantly from 26 % in 2003 to 6 % in 2012. A cost of $121,000 was expended on femoral heads failed post operatively in 2004, as compared to $20,350 in 2012. Donors excluded due to the 4 main categories (medical/social history) were identified pre-operatively in over 80 % of all cases. Preoperative screening of femoral head donors through a coordinated Femoral Head Donation Program is a safe and cost effective method.

Doxycycline in early CJD: a double-blinded randomised phase II and observational study.

PubMed

Varges, Daniela; Manthey, Henrike; Heinemann, Uta; Ponto, Claudia; Schmitz, Matthias; Schulz-Schaeffer, Walter J; Krasnianski, Anna; Breithaupt, Maren; Fincke, Fabian; Kramer, Katharina; Friede, Tim; Zerr, Inga

2017-02-01

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). 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. 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)). On the basis of our studies, a larger trial of doxycycline should be performed in persons in the earliest stages of CJD. EudraCT 2006-003934-14; Results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Donating blood for research: a potential method for enhancing customer satisfaction of permanently deferred blood donors.

PubMed

Waller, Daniel; Thijsen, Amanda; Garradd, Allira; Hayman, Jane; Smith, Geoff

2017-01-01

Each year, a large number of individuals in Australia are deferred from donating blood. A deferral may have a negative impact on donor satisfaction and subsequent word-of-mouth communication. The Australian Red Cross Blood Service (the Blood Service) is, therefore, investigating options for managing service interactions with deferred donors to maintain positive relationships. While public research institutes in Australia have established independent research donor registries, other countries provide programmes allowing deferred donors to donate blood for research via blood collection agencies. This study examined attitudes towards donating blood for research use in a sample of permanently deferred Australian donors. Donors permanently deferred because of a risk of variant Creutzfeldt-Jakob disease (n=449) completed a postal survey that examined attitudes towards research donation. The majority of participants were interested in donating blood for research (96%), and joining a registry of research donors (93%). Participants preferred to donate for transfusion or clinical research, and were willing to travel large distances. Results indicated that positive attitudes towards the Blood Service would be extended if the opportunity to donate blood was provided. These findings indicate a desire for continued engagement with the Blood Service despite deferral. Donating blood for research is a potential way of maintaining positive relationships with permanently deferred donors which also benefits the health research community. Through maintaining positive relationships with deferred donors, positive word-of-mouth activity can be stimulated. Further work is needed to determine the feasibility of implementing research donation through the Blood Service in Australia.

Donating blood for research: a potential method for enhancing customer satisfaction of permanently deferred blood donors

PubMed Central

Waller, Daniel; Thijsen, Amanda; Garradd, Allira; Hayman, Jane; Smith, Geoff

2017-01-01

Background Each year, a large number of individuals in Australia are deferred from donating blood. A deferral may have a negative impact on donor satisfaction and subsequent word-of-mouth communication. The Australian Red Cross Blood Service (the Blood Service) is, therefore, investigating options for managing service interactions with deferred donors to maintain positive relationships. While public research institutes in Australia have established independent research donor registries, other countries provide programmes allowing deferred donors to donate blood for research via blood collection agencies. This study examined attitudes towards donating blood for research use in a sample of permanently deferred Australian donors. Materials and methods Donors permanently deferred because of a risk of variant Creutzfeldt-Jakob disease (n=449) completed a postal survey that examined attitudes towards research donation. Results The majority of participants were interested in donating blood for research (96%), and joining a registry of research donors (93%). Participants preferred to donate for transfusion or clinical research, and were willing to travel large distances. Results indicated that positive attitudes towards the Blood Service would be extended if the opportunity to donate blood was provided. These findings indicate a desire for continued engagement with the Blood Service despite deferral. Discussion Donating blood for research is a potential way of maintaining positive relationships with permanently deferred donors which also benefits the health research community. Through maintaining positive relationships with deferred donors, positive word-of-mouth activity can be stimulated. Further work is needed to determine the feasibility of implementing research donation through the Blood Service in Australia. PMID:26674813

Development of a bifunctional filter for prion protein and leukoreduction of red blood cell components.

PubMed

Yokomizo, Tomo; Kai, Takako; Miura, Morikazu; Ohto, Hitoshi

2015-02-01

Leukofiltration of blood components is currently implemented worldwide as a precautionary measure against white blood cell-associated adverse effects and the potential transmission of variant Creutzfeldt-Jakob disease (vCJD). A newly developed bifunctional filter (Sepacell Prima, Asahi Kasei Medical) was assessed for prion removal, leukoreduction (LR), and whether the filter significantly affected red blood cells (RBCs). Sepacell Prima's postfiltration effects on RBCs, including hemolysis, complement activation, and RBC chemistry, were compared with those of a conventional LR filter (Sepacell Pure RC). Prion removal was measured by Western blot after spiking RBCs with microsomal fractions derived from scrapie-infected hamster brain homogenate. Serially diluted exogenous prion solutions (0.05 mL), with or without filtration, were injected intracerebrally into Golden Syrian hamsters. LR efficiency of 4.44 log with the Sepacell Prima was comparable to 4.11 log with the conventional LR filter. There were no significant differences between the two filters in hemoglobin loss, hemolysis, complement activation, and RBC biomarkers. In vitro reduction of exogenously spiked prions by the filter exceeded 3 log. The titer, 6.63 (log ID50 /mL), of prefiltration infectivity of healthy hamsters was reduced to 2.52 (log ID50 /mL) after filtration. The reduction factor was calculated as 4.20 (log ID50 ). With confirmed removal efficacy for exogenous prion protein, this new bifunctional prion and LR filter should reduce the residual risk of vCJD transmission through blood transfusion without adding complexity to component processing. © 2014 AABB.

Infections and exposures: reported incidents associated with unsuccessful decontamination of reusable surgical instruments.

PubMed

Southworth, P M

2014-11-01

Reusable surgical instruments provide a potential route for the transmission of pathogenic agents between patients in healthcare facilities. As such, the decontamination process between uses is a vital component in the prevention of healthcare-associated infections. This article reviews reported outbreaks and incidents associated with inappropriate, inadequate, or unsuccessful decontamination of surgical instruments, indicating potential pitfalls of decontamination practices worldwide. To the author's knowledge, this is the first review of surgical instrument decontamination failures. Databases of medical literature, Medline and Embase, were searched systematically. Articles detailing incidents associated with unsuccessful decontamination of surgical instruments were identified. Twenty-one articles were identified reporting incidents associated with failures in decontamination. A large proportion of incidents involved the attempted disinfection, rather than sterilization, of surgical instruments (43% of articles), counter to a number of national guidelines. Instruments used in eye surgery were most frequently reported to be associated with decontamination failures (29% of articles). Of the few articles detailing potential or confirmed pathogenic transmission, Pseudomonas aeruginosa and Mycobacterium spp. were most represented. One incident of possible variant Creutzfeldt-Jakob disease transmission was also identified. Limitations of analysing only published incidents mean that the likelihood of under-reporting (including reluctance to publish failure) must be considered. Despite these limitations, the small number of articles identified suggests a relatively low risk of cross-infection through reusable surgical instruments when cleaning/sterilization procedures are adhered to. The diverse nature of reported incidents also suggests that failures are not systemic. Copyright © 2014 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

[Electroencephalography and epileptology in the 20th century].

PubMed

Karbowski, K

1995-12-05

In 1875, Caton was already able to detect cerebral electric currents during experimental studies in animals. In 1914, Cybulski and Jeleńska-Macieszyna reported on the increase of current-intensity during a focal motor epileptic seizure. In 1929 in Jena, Berger revolutionized the study of epilepsy with his paper on the human electroencephalogram 'Uber das Elektrenkephalogramm des Menschen'. His discovery and further publications as well as later works of numerous researchers, especially F. and E. Gibbs, Lennox, Penfield and Jasper, made it possible to distinguish different forms of 'little' epileptic seizures and to separate them from nonepileptic paroxysmal disorders. New epileptic syndromes could be singled out, as e.g. the symptomatic epilepsy of childhood with variable clinical manifestations of seizures and slow spike-wave complexes in the EEG (Lennox-Gastaut syndrome) or the benign partial epilepsy of childhood with centrotemporal EEG spikes. In these fields, as well as for the epileptic seizures in newborns and babies and for the differentiation between epileptic and nonepileptic twilight states in later stages of life, the EEG remains an indispensable tool in the CT and MRI era. It also contributes largely to the diagnosis of nonepileptic cerebral illness such as herpes simplex encephalitis, subacute sclerosing panencephalitis van Bogaert and Creutzfeldt-Jakob disease. Since the introduction of phenobarbital by Hauptmann in 1912, the palet of effective drugs against epilepsy, such as phenytoin, carbamazepine, valproate and benzodiazepines used for status-epilepticus treatment, became essentially larger. The value of newer substances (vigabatrin, progabide, gabapentin, lamotrigin) can't be estimated actually.(ABSTRACT TRUNCATED AT 250 WORDS)

The Impact of Creutzfeldt–Jakob Disease on Surgical Practice

PubMed Central

Lumley, John SP

2008-01-01

Creutzfeldt–Jakob disease (CJD) is characterised by abnormal prion protein that can replicate and replace nervous tissue, with rapid lethal neurodegenerative consequences. The transmissible nature of CJD has been known for half a century and transmission has occurred through neurosurgical procedures. Variant Creutzfeldt–Jakob disease (vCJD) emerged in 1996, and the presence of abnormal prion in lymphatic tissue extended the number of surgical specialties dealing with infected material; transmission through blood transfusion raised the possibilities of a large carrier pool and spread of epidemic proportion. The abnormal prion is difficult to remove and this could influence future decontamination programmes. Contaminated instruments must be withdrawn from surgical practice, and this can interfere with the efficient running of a surgical unit and optimal patient care. There is an urgent need for reliable methods for the detection of abnormal prion, within and outside the body. These will help to clarify the epidemiology of CJD, and to reduce its transmission via blood and tissue. They will also allow determination of the efficacy of new decontamination products in surgical practice, and the value of any treatment of sufferers and carriers of CJD. In the meantime, continued vigilance and informed regulation of all aspects of CJD must remain. PMID:18325202

Hashimoto's encephalopathy : epidemiology, pathogenesis and management.

PubMed

Mocellin, Ramon; Walterfang, Mark; Velakoulis, Dennis

2007-01-01

Hashimoto's encephalopathy is a term used to describe an encephalopathy of presumed autoimmune origin characterised by high titres of antithyroid peroxidase antibodies. In a similar fashion to autoimmune thyroid disease, Hashimoto's encephalopathy is more common in women than in men. It has been reported in paediatric, adult and elderly populations throughout the world. The clinical presentation may involve a relapsing and remitting course and include seizures, stroke-like episodes, cognitive decline, neuropsychiatric symptoms and myoclonus. Thyroid function is usually clinically and biochemically normal.Hashimoto's encephalopathy appears to be a rare disorder, but, as it is responsive to treatment with corticosteroids, it must be considered in cases of 'investigation negative encephalopathies'. Diagnosis is made in the first instance by excluding other toxic, metabolic and infectious causes of encephalopathy with neuroimaging and CSF examination. Neuroimaging findings are often not helpful in clarifying the diagnosis. Common differential diagnoses when these conditions are excluded are Creutzfeldt-Jakob disease, rapidly progressive dementias, and paraneoplastic and nonparaneoplastic limbic encephalitis. In the context of the typical clinical picture, high titres of antithyroid antibodies, in particular antithyroid peroxidase antibodies, are diagnostic. These antibodies, however, can be detected in elevated titres in the healthy general population. Treatment with corticosteroids is almost always successful, although relapse may occur if this treatment is ceased abruptly. Other forms of immunomodulation, such as intravenous immune-globulin and plasma exchange, may also be effective. Despite the link to autoimmune thyroid disease, the aetiology of Hashimoto's encephalopathy is unknown. It is likely that antithyroid antibodies are not pathogenic, but titres can be a marker of treatment response. Pathological findings can suggest an inflammatory process, but features of a severe vasculitis are often absent. The links between the clinical pictures, thyroid disease, auto-antibody pattern and brain pathology await further clarification through research. It may be that Hashimoto's encephalopathy will be subsumed into a group of nonvasculitic autoimmune inflammatory meningoencephalopathies. This group may include disorders such as limbic encephalitis associated with voltage-gated potassium channel antibodies. Some authors have suggested abandoning any link to Hashimoto and renaming the condition 'steroid responsive encephalopathy associated with autoimmune thyroiditis' to better reflect current, if limited, understanding of this condition.

Prion Protein Regulates Iron Transport by Functioning as a Ferrireductase

PubMed Central

Singh, Ajay; Haldar, Swati; Horback, Katharine; Tom, Cynthia; Zhou, Lan; Meyerson, Howard; Singh, Neena

2017-01-01

Prion protein (PrPC) is implicated in the pathogenesis of prion disorders, but its normal function is unclear. We demonstrate that PrPC is a ferrireductase (FR), and its absence causes systemic iron deficiency in PrP knock-out mice (PrP−/−). When exposed to non-transferrin-bound (NTB) radioactive-iron (59FeCl3) by gastric-gavage, PrP−/− mice absorb significantly more 59Fe from the intestinal lumen relative to controls, indicating appropriate systemic response to the iron deficiency. Chronic exposure to excess dietary iron corrects this deficiency, but unlike wild-type (PrP+/+) controls that remain iron over-loaded, PrP−/− mice revert back to the iron deficient phenotype after 5 months of chase on normal diet. Bone marrow (BM) preparations of PrP−/− mice on normal diet show relatively less stainable iron, and this phenotype is only partially corrected by intraperitoneal administration of excess iron-dextran. Cultured PrP−/− BM-macrophages incorporate significantly less NTB-59Fe in the absence or presence of excess extracellular iron, indicating reduced uptake and/or storage of available iron in the absence of PrPC. When expressed in neuroblastoma cells, PrPC exhibits NAD(P)H-dependent cell-surface and intracellular FR activity that requires the copper-binding octa-peptide-repeat region and linkage to the plasma membrane for optimal function. Incorporation of NTB-59Fe by neuroblastoma cells correlates with FR activity of PrPC, implicating PrPC in cellular iron uptake and metabolism. These observations explain the correlation between PrPC expression and cellular iron levels, and the cause of iron imbalance in sporadic-Creutzfeldt-Jakob-disease brains where PrPC accumulates as insoluble aggregates. PMID:23478311

Copper brain protein protection against free radical-induced neuronal death: Survival ratio in SH-SY5Y neuroblastoma cell cultures.

PubMed

Deloncle, Roger; Fauconneau, Bernard; Guillard, Olivier; Delaval, José; Lesage, Gérard; Pineau, Alain

2017-01-01

In Creutzfeldt Jakob, Alzheimer and Parkinson diseases, copper metalloproteins such as prion, amyloid protein precursor and α-synuclein are able to protect against free radicals by reduction from cupric Cu +2 to cupreous Cu + . In these pathologies, a regional copper (Cu) brain decrease correlated with an iron, zinc or manganese (Mn) increase has previously been observed, leading to local neuronal death and abnormal deposition of these metalloproteins in β-sheet structures. In this study we demonstrate the protective effect of Cu metalloproteins against deleterious free-radical effects. With neuroblastoma SH-SY5Y cell cultures, we show that bovine brain prion protein in Cu but not Mn form prevents free radical-induced neuronal death. The survival ratio of SH-SY5Y cells has been measured after UV irradiation (free radical production), when the incubating medium is supplemented with bovine brain homogenate in native, Cu or Mn forms. This ratio, about 28% without any addition or with bovine brain protein added in Mn form, increases by as much as 54.73% with addition to the culture medium of native bovine brain protein and by as much as 95.95% if the addition is carried out in cupric form. This protective effect of brain copper protein against free radical-induced neuronal death has been confirmed with Inductively Coupled Plasma Mass Spectrometry Mn and Cu measurement in bovine brain homogenates: respectively lower than detection limit and 9.01μg/g dry weight for native form; lower than detection limit and 825.85μg/g dry weight for Cu-supplemented form and 1.75 and 68.1μg/g dry weight in Mn-supplemented brain homogenate. Copyright © 2016 Elsevier GmbH. All rights reserved.

Evaluation of rapid post-mortem test kits for bovine spongiform encephalopathy (BSE) screening in Japan: Their analytical sensitivity to atypical BSE prions.

PubMed

Hagiwara, Ken'ichi; Iwamaru, Yoshifumi; Tabeta, Naoko; Yokoyama, Takashi; Tobiume, Minoru

2017-03-04

A classical type of bovine spongiform encephalopathy (C-BSE), recognized in 1987, had a large impact on public health due to its zoonotic link to variant Creutzfeldt-Jakob disease by the human consumption of dietary products contaminated with the C-BSE prion. Thus, a number of countries implemented BSE surveillance using rapid post-mortem test kits that were approved for detection of the C-BSE prion in the cattle brain. However, as atypical BSE (L- and H-BSE) cases emerged in subsequent years, the efficacy of the kits for the detection of atypical BSE prions became a matter of concern. In response to this, laboratories in the European Union and Canada evaluated the kits used in their countries. Here, we carried out an evaluation study of NippiBL®, a kit currently used for BSE screening in Japan. By applying the kit to cattle brains of field cases of C-BSE and L-BSE, and an experimental case of H-BSE, we showed its comparable sensitivities to C, L-, and H-BSE prions, and satisfactory performance required by the European Food Safety Authority. In addition to NippiBL®, two kits (TeSeE® and FRELISA®) formerly used in Japan were effective for detection of the L-BSE prion, although the two kits were unable to be tested for the H-BSE prion due to the discontinuation of domestic sales during this study. These results indicate that BSE screening in Japan is as effective as those in other countries, and it is unlikely that cases of atypical BSE have been overlooked.

Prion removal effect of a specific affinity ligand introduced into the manufacturing process of the pharmaceutical quality solvent/detergent (S/D)-treated plasma OctaplasLG.

PubMed

Neisser-Svae, A; Bailey, A; Gregori, L; Heger, A; Jordan, S; Behizad, M; Reichl, H; Römisch, J; Svae, T-E

2009-10-01

A new chromatographic step for the selective binding of abnormal prion protein (PrP(Sc)) was developed, and optimization for PrP(Sc) capture was achieved by binding to an affinity ligand attached to synthetic resin particles. This step was implemented into the manufacturing process of the solvent/detergent (S/D)-treated biopharmaceutical quality plasma Octaplas to further improve the safety margin in terms of risk for variant Creutzfeldt-Jakob disease (vCJD) transmission. Intermediates and Octaplas final container material, spiked with hamster brain-derived PrP(Sc)-containing fractions, were used for experiments to establish the feasibility of introducing this novel chromatography step. The binding capacity per millilitre of ligand gel was determined under the selected manufacturing conditions. In addition, the specificity of the ligand gel to bind PrP(Sc) from human sources was investigated. A validated Western blot test was used for the identification and quantification of PrP(Sc). A reduction factor of > or = 3.0 log(10) could be demonstrated by Western blotting, utilizing the relevant Octaplas matrix from manufacturing. In this particular cell-free plasma solution, the PrP(Sc) binding capacity of the selected gel was very high (> or = 6 log(10) ID(50)/ml, equivalent to roughly 10 log(10) ID(50)/column at manufacturing scale). The gel binds specifically PrP(Sc) from both animal (hamster and mouse) and human (sporadic and variant CJD) sources. This new single-use, disposable PrP(Sc)-harvesting gel ensures a very high capacity in terms of removing the pathogenic agent causing vCJD from the new generation OctaplasLG, in the event that prions can be found in plasma from donors incubating the disease and thereby contaminating the raw material plasma used for manufacturing.

The National Heart, Lung, and Blood Institute retrovirus epidemiology donor studies (Retrovirus Epidemiology Donor Study and Retrovirus Epidemiology Donor Study-II): twenty years of research to advance blood product safety and availability.

PubMed

Kleinman, Steven; King, Melissa R; Busch, Michael P; Murphy, Edward L; Glynn, Simone A

2012-10-01

The Retrovirus Epidemiology Donor Study (REDS), conducted from 1989 to 2001, and the REDS-II, conducted from 2004 to 2012, were National Heart, Lung, and Blood Institute-funded, multicenter programs focused on improving blood safety and availability in the United States. The REDS-II also included international study sites in Brazil and China. The 3 major research domains of REDS/REDS-II have been infectious disease risk evaluation, blood donation availability, and blood donor characterization. Both programs have made significant contributions to transfusion medicine research methodology by the use of mathematical modeling, large-scale donor surveys, innovative methods of repository sample storage, and establishing an infrastructure that responded to potential emerging blood safety threats such as xenotropic murine leukemia virus-related virus. Blood safety studies have included protocols evaluating epidemiologic and/or laboratory aspects of human immunodeficiency virus, human T-lymphotropic virus 1/2, hepatitis C virus, hepatitis B virus, West Nile virus, cytomegalovirus, human herpesvirus 8, parvovirus B19, malaria, Creutzfeldt-Jakob disease, influenza, and Trypanosoma cruzi infections. Other analyses have characterized blood donor demographics, motivations to donate, factors influencing donor return, behavioral risk factors, donors' perception of the blood donation screening process, and aspects of donor deferral. In REDS-II, 2 large-scale blood donor protocols examined iron deficiency in donors and the prevalence of leukocyte antibodies. This review describes the major study results from over 150 peer-reviewed articles published by these 2 REDS programs. In 2011, a new 7-year program, the Recipient Epidemiology and Donor Evaluation Study-III, was launched. The Recipient Epidemiology and Donor Evaluation Study-III expands beyond donor-based research to include studies of blood transfusion recipients in the hospital setting and adds a third country, South Africa, to the international program. Copyright © 2012 Elsevier Inc. All rights reserved.

Autoimmune encephalitis associated with voltage-gated potassium channels-complex and leucine-rich glioma-inactivated 1 antibodies - a national cohort study.

PubMed

Celicanin, M; Blaabjerg, M; Maersk-Moller, C; Beniczky, S; Marner, L; Thomsen, C; Bach, F W; Kondziella, D; Andersen, H; Somnier, F; Illes, Z; Pinborg, L H

2017-08-01

The aim of this study was to describe clinical and paraclinical characteristics of all Danish patients who tested positive for anti-voltage-gated potassium channels (VGKC)-complex, anti-leucine-rich glioma-inactivated 1 (LGI1) and anti-contactin-associated protein-2 antibodies in the serum/cerebrospinal fluid between 2009 and 2013 with follow-up interviews in 2015 and 2016. We evaluated antibody status, symptoms leading to testing, course of disease, suspected diagnosis and time of admission as well as diagnosis and treatment. All magnetic resonance imaging, electroencephalography and 18 F-fluorodeoxyglucose positron emission tomography scans were re-evaluated by experts in the field. A total of 28/192 patients tested positive for VGKC-complex antibodies by radioimmunoassay and indirect immunofluorescence; 17 had antibodies to LGI1 and 6/7 of the available cerebrospinal fluids from these patients were seropositive. These 17 patients all had a clinical phenotype appropriate to LGI1 antibodies. The remaining 11 were LGI1 negative (n = 4) or not tested (n = 7). Of these, two had a phenotype consistent with limbic encephalitis. The remaining phenotypes were Guillain-Barré syndrome, Creutzfeldt-Jakob disease, neuromyotonia and anti-N-methyl-D-aspartate receptor encephalitis. Magnetic resonance imaging abnormalities were demonstrated in 69% of the LGI1-positive patients. Two patients with normal magnetic resonance imaging demonstrated temporal lobe hypermetabolism using 18 F-fluorodeoxyglucose positron emission tomography. Abnormal electroencephalography recordings were found in 86% of the patients. Upon follow-up (median 3.2 years), the median modified Rankin Scale score of anti-LGI1-positive patients was 2 and only two patients reported seizures in the past year. Patients diagnosed with anti-LGI1 autoimmune encephalitis increased significantly from 2009 to 2014, probably due to increased awareness. In contrast to seropositive anti-VGKC-complex patients, all anti-LGI1-positive patients presented with a classical limbic encephalitis. The majority of patients recovered well. © 2017 EAN.

Comparison of candidate vCJD in vitro diagnostic assays using identical sample sets.

PubMed

Cooper, J K; Ladhani, K; Minor, P

2012-02-01

With four transfusion related transmissions of variant Creutzfeldt-Jakob Disease (vCJD), three of which developed clinical disease and the other died of other causes but was positive for markers of infection, there is an increased urgency to identify and implement a test for blood donor screening. With limited amounts of blood samples from vCJD cases available test evaluation is challenging. Alternative approaches are therefore needed. Control and vCJD tissues homogenates, where levels of markers of infectivity are known, were sequentially diluted in pooled human plasma. Identical sets of samples were provided blind to research groups developing diagnostic tests for vCJD; identical sample sets allows for direct comparisons of sensitivity to be made. Control and vCJD tissue homogenates were sequentially diluted in pooled human plasma (detergent solvent treated or cryo-depleted) supplied by commercial fractionators. Dilutions of vCJD tissues were within and beyond the limits of detection previously determined by the conformation-dependent immunoassay (Cooper et al.: Vox Sang 2007;92:302-310; Bellon et al.: J Gen Virol 2003;84: 1921-1925). A number of methods were used for the analysis of the blinded panels; with background signal from the normal prion protein (PrP) being removed by digestion with proteinase, epitope protection or selective capture of PrP(tse). Assay sensitivities were directly compared using identical sample sets. This approach identified several transmissible spongiform encephalopathies (TSE) diagnostic tests, based on different principles, high in analytical sensitivity that reproducibly detected markers of vCJD infectivity in tissue homogenates. The approach outlined has successfully compared in vitro diagnostics assays for their sensitivity and reproducibility and is a first step toward the evaluation of an assay suitable for blood donor screening/diagnosis of vCJD. © 2011 The Author(s). Vox Sanguinis © 2011 International Society of Blood Transfusion.

Inactivation of Prions and Amyloid Seeds with Hypochlorous Acid

PubMed Central

Kraus, Allison; Phillips, Katie; Contreras, Luis; Zanusso, Gianluigi; Caughey, Byron

2016-01-01

Hypochlorous acid (HOCl) is produced naturally by neutrophils and other cells to kill conventional microbes in vivo. Synthetic preparations containing HOCl can also be effective as microbial disinfectants. Here we have tested whether HOCl can also inactivate prions and other self-propagating protein amyloid seeds. Prions are deadly pathogens that are notoriously difficult to inactivate, and standard microbial disinfection protocols are often inadequate. Recommended treatments for prion decontamination include strongly basic (pH ≥~12) sodium hypochlorite bleach, ≥1 N sodium hydroxide, and/or prolonged autoclaving. These treatments are damaging and/or unsuitable for many clinical, agricultural and environmental applications. We have tested the anti-prion activity of a weakly acidic aqueous formulation of HOCl (BrioHOCl) that poses no apparent hazard to either users or many surfaces. For example, BrioHOCl can be applied directly to skin and mucous membranes and has been aerosolized to treat entire rooms without apparent deleterious effects. Here, we demonstrate that immersion in BrioHOCl can inactivate not only a range of target microbes, including spores of Bacillus subtilis, but also prions in tissue suspensions and on stainless steel. Real-time quaking-induced conversion (RT-QuIC) assays showed that BrioHOCl treatments eliminated all detectable prion seeding activity of human Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, cervine chronic wasting disease, sheep scrapie and hamster scrapie; these findings indicated reductions of ≥103- to 106-fold. Transgenic mouse bioassays showed that all detectable hamster-adapted scrapie infectivity in brain homogenates or on steel wires was eliminated, representing reductions of ≥~105.75-fold and >104-fold, respectively. Inactivation of RT-QuIC seeding activity correlated with free chlorine concentration and higher order aggregation or destruction of proteins generally, including prion protein. BrioHOCl treatments had similar effects on amyloids composed of human α-synuclein and a fragment of human tau. These results indicate that HOCl can block the self-propagating activity of prions and other amyloids. PMID:27685252

Kuru prions and sporadic Creutzfeldt–Jakob disease prions have equivalent transmission properties in transgenic and wild-type mice

PubMed Central

Wadsworth, Jonathan D. F.; Joiner, Susan; Linehan, Jacqueline M.; Desbruslais, Melanie; Fox, Katie; Cooper, Sharon; Cronier, Sabrina; Asante, Emmanuel A.; Mead, Simon; Brandner, Sebastian; Hill, Andrew F.; Collinge, John

2008-01-01

Kuru provides our principal experience of an epidemic human prion disease and primarily affected the Fore linguistic group of the Eastern Highlands of Papua New Guinea. Kuru was transmitted by the practice of consuming dead relatives as a mark of respect and mourning (transumption). To date, detailed information of the prion strain type propagated in kuru has been lacking. Here, we directly compare the transmission properties of kuru prions with sporadic, iatrogenic, and variant Creutzfeldt–Jakob disease (CJD) prions in Prnp-null transgenic mice expressing human prion protein and in wild-type mice. Molecular and neuropathological data from these transmissions show that kuru prions are distinct from variant CJD and have transmission properties equivalent to those of classical (sporadic) CJD prions. These findings are consistent with the hypothesis that kuru originated from chance consumption of an individual with sporadic CJD. PMID:18316717

[The research advances and applications of genome editing in hereditary eye diseases].

PubMed

Cai, S W; Zhang, Y; Hou, M Z; Liu, Y; Li, X R

2017-05-11

Genome editing is a cutting-edge technology that generates DNA double strand breaks at the specific genomic DNA sequence through nuclease recognition and cleavage, and then achieves insertion, replacement, or deletion of the target gene via endogenous DNA repair mechanisms, such as non-homologous end joining, homology directed repair, and homologous recombination. So far, more than 600 human hereditary eye diseases and systemic hereditary diseases with ocular phenotypes have been found. However, most of these diseases are of incompletely elucidated pathogenesis and without effective therapies. Genome editing technology can precisely target and alter the genomes of animals, establish animal models of the hereditary diseases, and elucidate the relationship between the target gene and the disease phenotype, thereby providing a powerful approach to studying the pathogenic mechanisms underlying the hereditary eye diseases. In addition, correction of gene mutations by the genome editing brings a new hope to gene therapy for the hereditary eye diseases. This review introduces the molecular characteristics of 4 major enzymes used in the genome editing, including homing endonucleases, zinc finger nucleases, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR-associated protein 9 (Cas9), and summarizes the current applications of this technology in investigating the pathogenic mechanisms underlying the hereditary eye diseases. (Chin J Ophthalmol, 2017, 53: 386-371 ) .

Protein aggregation and prionopathies.

PubMed

Renner, M; Melki, R

2014-06-01

Prion protein and prion-like proteins share a number of characteristics. From the molecular point of view, they are constitutive proteins that aggregate following conformational changes into insoluble particles. These particles escape the cellular clearance machinery and amplify by recruiting the soluble for of their constituting proteins. The resulting protein aggregates are responsible for a number of neurodegenerative diseases such as Creutzfeldt-Jacob, Alzheimer, Parkinson and Huntington diseases. In addition, there are increasing evidences supporting the inter-cellular trafficking of these aggregates, meaning that they are "transmissible" between cells. There are also evidences that brain homogenates from individuals developing Alzheimer and Parkinson diseases propagate the disease in recipient model animals in a manner similar to brain extracts of patients developing Creutzfeldt-Jacob's disease. Thus, the propagation of protein aggregates from cell to cell may be a generic phenomenon that contributes to the evolution of neurodegenerative diseases, which has important consequences on human health issues. Moreover, although the distribution of protein aggregates is characteristic for each disease, new evidences indicate the possibility of overlaps and crosstalk between the different disorders. Despite the increasing evidences that support prion or prion-like propagation of protein aggregates, there are many unanswered questions regarding the mechanisms of toxicity and this is a field of intensive research nowadays. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Exploring the quality of life issues in people with retinal diseases: a qualitative study.

PubMed

Prem Senthil, Mallika; Khadka, Jyoti; Gilhotra, Jagjit Singh; Simon, Sumu; Pesudovs, Konrad

2017-01-01

The lack of an appropriate retina-specific patient-reported outcome instrument restricts the understanding of the full impact of hereditary retinal diseases and other less common but potentially blinding acquired retinal diseases such as, vascular occlusions, epiretinal membrane, macular hole, central serous retinopathy and other vitreoretinopathies on quality of life. This study aims to explore the quality of life issues in people with hereditary retinal diseases and acquired retinal diseases to develop disease-specific patient-reported outcome instruments. A qualitative research methodology to understand the lived experiences of people with retinal diseases was carried out. Data were collected through semistructured interviews. The coding, aggregation and theme development was carried out using the NVivo -10 software. Seventy-nine interviews were conducted with participants with hereditary retinal diseases ( n  = 32; median age = 57 years) and acquired retinal diseases ( n  = 47; median age = 73 years). We identified nine quality of life themes (domains) relevant to people with retinal diseases. Difficulty in performing important day-to-day activities (activity limitation) was the most prominent quality of life issue in the hereditary retinal diseases group whereas concerns about health, disease outcome and personal safety (health concerns) was the most prominent quality of life issue in the acquired retinal diseases group. Participants with hereditary retinal diseases had more issues with social interaction (social well-being), problems with mobility and orientation (mobility), and effect on work and finance (economic) than participants with acquired retinal diseases. On the contrary, participants with acquired retinal diseases reported more inconveniences (conveniences) than participants with hereditary retinal diseases, which were mostly attributed to treatment. Participants with hereditary retinal diseases were coping better compared to participants with acquired retinal diseases. Our study found that participants with both hereditary and acquired retinal diseases are living with myriad of disease-specific quality of life issues. Many of these issues are completely different and unique to each disease group. Hence, these group of diseases would need separate patient-reported outcome instruments to capture the disease-specific quality of life impacts.

Verses, viruses, and the vulnerability of the blood supply in industrialized countries.

PubMed

Mushahwar, Isa K

2007-08-01

In the last 30 years, tremendous progress in identifying transfusion-transmitted viruses such as HBV, HCV, and HIV in industrialized countries has been achieved. Currently, the residual risk of transmitting these viruses through transfusion is very low especially after the introduction of "minipool" nucleic acid-amplification tests. Despite these major technical advances, there remains a legitimate concern as to the transmission of other blood-borne infectious agents through blood transfusion. Among these agents are HBV mutants, occult HBV, and HCV infections, malaria, Chagas, West Nile, dengue, and vesiviruses, bacterial infections such as Yersinia enterocolitica, and tick borne diseases such as human monocytic ehrlichiosis, human granulocytic ehrlichiosis, Rocky Mountain spotted fever, and Lyme and prion diseases such as Creutzfeldt and variant Creutzfeldt. Most of these agents are very rarely transmitted by transfusion in industrialized countries. However, an awareness of their possible transmission is essential for the control of spread of these diseases among the public by human-to-human transmission via blood transfusion. This review summarizes the current status of prevalence and diagnosis of these emerging diseases and also updates our knowledge on recently discovered non-pathogenic blood-borne viruses such as GB virus C and Torque Tenoviruses.

The growth hormone cascade: progress and long-term results of growth hormone treatment in growth hormone deficiency.

PubMed

Grumbach, M M; Bin-Abbas, B S; Kaplan, S L

1998-01-01

The growth hormone (GH) cascade and the remarkable advances over the past four decades in our knowledge of its components are considered. It is now over 40 years since human pituitary GH (pit-hGH) was purified and the first GH-deficient patient, a 17-year-old male, was successfully treated with pit-hGH. However, the shortage of pit-hGH limited its use and the dose, the biopotency of preparations varied, strict criteria of GH deficiency (GHD) were used for patient selection including peak plasma immunoreactive GH levels after provocative stimuli of <3.5-5 ng/ml, treatment was not infrequently interrupted, the mean age for initiating treatment was often late in childhood (12-13 years) and the growth deficiency severe (height -4 to -6 SDS), and finally pit-hGH therapy was often discontinued when girls attained a height of 5' and boys 5'5". Nonetheless, the effects of pit-hGH were dramatic; the final height SDS increased in isolated GHD to about -2 SDS in boys and -2.5 to -3.0 SDS in girls, and in multiple pituitary hormone deficiencies to between -1 and -2 SDS. Between 1962 and 1985 when the Creutzfeldt-Jakob disease crisis struck, the number of GH-deficient patients treated with pit-hGH increased from about 150 to over 3,000. The advent of biosynthetic GH (rhGH) and its availability to treat large numbers of idiopathic GH-deficient children (the minimum prevalence rate of which in the USA and UK is between 1 in 3,400 and 4,000) dramatically changed this picture in 1985. It is estimated that more than 60,000 patients have been or are now on treatment. With rhGH treatment the attained mean adult height SDS is now about -1.0, and in our experience with the treatment of patients under 4 years of age, final height may exceed the target height. It is now recognized that (a) the replacement dose of rhGH ranges from 0.175 to 0.35 mg/kg/week and should be individualized; (b) dividing this dose into 6 or 7 daily subcutaneous injections is more effective than giving the same total dose in three weekly portions, and (c) final height correlates significantly with pretreatment chronologic age, height SDS and predicted adult height, duration of therapy, birth length, in some studies height SDS and age at start of puberty, weight, and serum GHBP (an indicator of GH receptor mass). Early recognition of GHD is essential for an optimal height outcome. rhGH treatment should not be delayed in children with documented GHD; the greater the height deficit, the lower the probability that target height will be reached. GHD needs to be detected earlier in children with organic hypopituitarism whether due to a developmental defect, neoplasm, radiation, head trauma, or a CNS infection. Early rhGH therapy in neonatal hypopituitarism has resulted in excellent growth responses. As the height prognosis in isolated GHD is not as good (especially in girls) as in GHD associated with gonadotropin deficiency, the use of LHRH agonists to delay puberty or potent aromatase inhibitors to delay skeletal maturation should be considered in selected patients with isolated GHD. When the growth response to rhGH is less than predicted, one must consider: (a) poor compliance; (b) improper preparation of rhGH for administration or faulty injection techniques; (c) the timing of administration; (d) the dose of glucocorticoid in the ACTH-deficient patient; (e) occult hypothyroidism; (f) inadequate nutrition; (g) a chronic illness; (h) neutralizing antibodies to rhGH, and (i) the wrong diagnosis. The major cause of mortality (unrelated to Creutzfeldt-Jakob disease or a CNS neoplasm) is adrenal crisis and hypoglycemia in children with both GH and ACTH deficiency. Major adverse effects of rhGH treatment in children are uncommon and include idiopathic intracranial hypertension, slipped capital femoral epiphysis, and acute pancreatitis. The rhGH is not an added risk for leukemia in the US and Europe in the absence of coexisting risk factors, nor is there a higher risk of recurrence of b

Brazilian guidelines for the diagnosis and treatment of hereditary angioedema.

PubMed

Giavina-Bianchi, Pedro; França, Alfeu T; Grumach, Anete S; Motta, Abílio A; Fernandes, Fátima R; Campos, Regis A; Valle, Solange O; Rosário, Nelson A; Sole, Dirceu

2011-01-01

Hereditary angioedema is an autosomal dominant disease characterized by edema attacks with multiple organ involvement. It is caused by a quantitative or functional deficiency of the C1 inhibitor, which is a member of the serine protease inhibitor family. Hereditary angioedema is unknown to many health professionals and is therefore an underdiagnosed disease. The causes of death from hereditary angioedema include laryngeal edema with asphyxia. The estimated mortality rate in patients in whom the disease goes undetected and who are therefore incorrectly treated is 25-40%. In addition to edema of the glottis, hereditary angioedema often results in edema of the gastrointestinal tract, which can be incapacitating. Patients with hereditary angioedema may undergo unnecessary surgical interventions because the digestive tract can be the primary or only organ system involved, thus mimicking acute surgical abdomen. It is estimated that patients with hereditary angioedema experience some degree of disability 20-100 days per year. The Experts in Clinical Immunology and Allergy of the "Associação Brasileira de Alergia e Imunopatologia -ASBAI" developed these guidelines for the diagnosis, therapy, and management of hereditary angioedema.

Bovine spongiform encephalopathy: "mad cow disease".

PubMed

1996-07-01

Bovine spongiform encephalopathy (BSE), also known as "mad cow disease," is a fatal brain disease of cattle first recognized in the United Kingdom. In humans, the most common transmissible spongiform encephalopathy is Creutzfeldt-Jacob Disease (CJD). Although no cases of CJD have been directly linked to beef consumption, an advisory committee has reported that 10 recent cases of a CJD variant may be associated with BSE. This announcement has alarmed consumers well beyond the borders of the United Kingdom.

Mathematical models for the diffusion magnetic resonance signal abnormality in patients with prion diseases.

PubMed

Figini, Matteo; Alexander, Daniel C; Redaelli, Veronica; Fasano, Fabrizio; Grisoli, Marina; Baselli, Giuseppe; Gambetti, Pierluigi; Tagliavini, Fabrizio; Bizzi, Alberto

2015-01-01

In clinical practice signal hyperintensity in the cortex and/or in the striatum on magnetic resonance (MR) diffusion-weighted images (DWIs) is a marker of sporadic Creutzfeldt-Jakob Disease (sCJD). MR diagnostic accuracy is greater than 90%, but the biophysical mechanisms underpinning the signal abnormality are unknown. The aim of this prospective study is to combine an advanced DWI protocol with new mathematical models of the microstructural changes occurring in prion disease patients to investigate the cause of MR signal alterations. This underpins the later development of more sensitive and specific image-based biomarkers. DWI data with a wide a range of echo times and diffusion weightings were acquired in 15 patients with suspected diagnosis of prion disease and in 4 healthy age-matched subjects. Clinical diagnosis of sCJD was made in nine patients, genetic CJD in one, rapidly progressive encephalopathy in three, and Gerstmann-Sträussler-Scheinker syndrome in two. Data were analysed with two bi-compartment models that represent different hypotheses about the histopathological alterations responsible for the DWI signal hyperintensity. A ROI-based analysis was performed in 13 grey matter areas located in affected and apparently unaffected regions from patients and healthy subjects. We provide for the first time non-invasive estimate of the restricted compartment radius, designed to reflect vacuole size, which is a key discriminator of sCJD subtypes. The estimated vacuole size in DWI hyperintense cortex was in the range between 3 and 10 µm that is compatible with neuropathology measurements. In DWI hyperintense grey matter of sCJD patients the two bi-compartment models outperform the classic mono-exponential ADC model. Both new models show that T2 relaxation times significantly increase, fast and slow diffusivities reduce, and the fraction of the compartment with slow/restricted diffusion increases compared to unaffected grey matter of patients and healthy subjects. Analysis of the raw DWI signal allows us to suggest the following acquisition parameters for optimized detection of CJD lesions: b = 3000 s/mm(2) and TE = 103 ms. In conclusion, these results provide the first in vivo estimate of mean vacuole size, new insight on the mechanisms of DWI signal changes in prionopathies and open the way to designing an optimized acquisition protocol to improve early clinical diagnosis and subtyping of sCJD.

Comparative analysis of human tissue interactomes reveals factors leading to tissue-specific manifestation of hereditary diseases.

PubMed

Barshir, Ruth; Shwartz, Omer; Smoly, Ilan Y; Yeger-Lotem, Esti

2014-06-01

An open question in human genetics is what underlies the tissue-specific manifestation of hereditary diseases, which are caused by genomic aberrations that are present in cells across the human body. Here we analyzed this phenomenon for over 300 hereditary diseases by using comparative network analysis. We created an extensive resource of protein expression and interactions in 16 main human tissues, by integrating recent data of gene and protein expression across tissues with data of protein-protein interactions (PPIs). The resulting tissue interaction networks (interactomes) shared a large fraction of their proteins and PPIs, and only a small fraction of them were tissue-specific. Applying this resource to hereditary diseases, we first show that most of the disease-causing genes are widely expressed across tissues, yet, enigmatically, cause disease phenotypes in few tissues only. Upon testing for factors that could lead to tissue-specific vulnerability, we find that disease-causing genes tend to have elevated transcript levels and increased number of tissue-specific PPIs in their disease tissues compared to unaffected tissues. We demonstrate through several examples that these tissue-specific PPIs can highlight disease mechanisms, and thus, owing to their small number, provide a powerful filter for interrogating disease etiologies. As two thirds of the hereditary diseases are associated with these factors, comparative tissue analysis offers a meaningful and efficient framework for enhancing the understanding of the molecular basis of hereditary diseases.

Disinfection of Tonometers: A Report by the American Academy of Ophthalmology.

PubMed

Junk, Anna K; Chen, Philip P; Lin, Shan C; Nouri-Mahdavi, Kouros; Radhakrishnan, Sunita; Singh, Kuldev; Chen, Teresa C

2017-12-01

To examine the efficacy of various disinfection methods for reusable tonometer prisms in eye care and to highlight how disinfectants can damage tonometer tips and cause subsequent patient harm. Literature searches were conducted last in October 2016 in the PubMed and the Cochrane Library databases for original research investigations. Reviews, non-English language articles, nonophthalmology articles, surveys, and case reports were excluded. The searches initially yielded 64 unique citations. After exclusion criteria were applied, 10 laboratory studies remained for this review. Nine of the 10 studies used tonometer prisms and 1 used steel discs. The infectious agents covered in this assessment include adenovirus 8 and 19, herpes simplex virus (HSV) 1 and 2, human immunodeficiency virus 1, hepatitis C virus, enterovirus 70, and variant Creutzfeldt-Jakob disease. All 4 studies of adenovirus 8 concluded that after sodium hypochlorite (dilute bleach) disinfection, the virus was undetectable, but only 2 of the 4 studies found that 70% isopropyl alcohol (e.g., alcohol wipes or soaks) eradicated all viable virus. All 3 HSV studies concluded that both sodium hypochlorite and 70% isopropyl alcohol eliminated HSV. Ethanol, 70% isopropyl alcohol, dilute bleach, and mechanical cleaning all lack the ability to remove cellular debris completely, which is necessary to prevent prion transmission. Therefore, single-use tonometer tips or disposable tonometer covers should be considered when treating patients with suspected prion disease. Damage to tonometer prisms can be caused by sodium hypochlorite, 70% isopropyl alcohol, 3% hydrogen peroxide, ethyl alcohol, water immersion, ultraviolet light, and heat exposure. Disinfectants can cause tonometer tips to swell and crack by dissolving the glue that holds the hollow tip together. The tonometer tip cracks can irritate the cornea, harbor microbes, or allow disinfectants to enter the interior of the tonometer tip. Sodium hypochlorite (dilute bleach) offers effective disinfection against adenovirus and HSV, the viruses commonly associated with nosocomial outbreaks in eye care. Tonometer prisms should be examined regularly for signs of damage. Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Biodegradation of organophosphorus pesticides by soil bacteria

NASA Astrophysics Data System (ADS)

de Pasquale, C.; Fodale, R.; Lo Piccolo, L.; Palazzolo, E.; Alonzo, G.; Quatrini, P.

2009-04-01

A number of studies in the 1980s and 1990s showed that crop-protection products, applied to drained fields, could move downwards through the soil profile and to the groundwater. Organophosphorus insecticides (OPs) are used all over the world for crop protection, for other agricultural practices such as sheep dipping and, in aquaculture, for the control of sea lice. Ops besides showing a specific neurotoxicity and have also been related to various modern diseases, including Creutzfeldt-Jakob (CJD) and the Gulf War syndrome. Although OPs are less persistent than Organoclorine pesticides (OCs), they still constitute an environmental risks thus increasing the social concern about their levels in soils, surface waters, and ground waters. Degradation of OPs by microorganisms has been assessed for a few bacterial strains. In the present study the OPs degrading potential of indigenous soil microorganisms was investigated. Using enrichment cultures in which parathion was the only C and energy sources many bacterial strains were isolated from OPs contaminated and pristine agricultural soils characterized by different physico-chemical properties. More than 40 potential OPs degraders were isolated and grouped in operational taxonomic units (OTU) using analysis of polymorphism showed by the ribosomal internal transcribed spacer (ITS). Partial sequencing of 16S rRNA gene of representative isolates of each OTU revealed that most of them belong to Proteobacteria and Actinobacteria. All the analyzed soils showed the presence of putative OPs degraders: the highest diversity was found in organic cultivated soils, the lowest in chemically cultivated soils. Degradation of different OPs, characterized by different physical and chemical properties, was obtained by different selected representative strains using SPME GC-MS analysis on water and soil microcosms. The results showed that, after the incubation period, the amount of pesticide residues were in the range 20-80%. Some of the isolates bacterial species are currently unknown as OPs degraders.

Actions of the Japanese Pancreas and Islet Transplantation Association regarding transplanted human islets isolated using Liberase HI.

PubMed

Saito, T; Anazawa, T; Gotoh, M; Uemoto, S; Kenmochi, T; Kuroda, Y; Satomi, S; Itoh, T; Yasunami, Y; Kitamoto, T; Mohri, S; Teraoka, S

2010-12-01

The potential for introducing transmissible spongiform encephalopathy (TSE) into islet cells was indicated by recognizing that Liberase HI is isolated from Clostridium histolyticum grown in media containing brain-heart infusion broth. A national team within the Japanese Pancreas and Islet Transplantation Association implemented an islet transplantation program in Japan using Liberase HI. The program comprised 65 islet isolations from non-heart-beating donors and 34 transplants into 18 patients. Herein, we have summarized how the Association followed these recipients over the long term. We established an ad hoc committee to follow recipients transplanted with islets isolated using Liberase HI after becoming informed of the associated dangers of using this enzyme. We also stopped islet transplantations using Liberase. The committee addressed the major concerns of the risk of the collagenase being contaminated with TSE and of the recipient follow-up. All recipients were examined by diffusion MRI and EEG and then scheduled for evaluation and follow-up by specialists in Creutzfeldt-Jakob disease (CJD). Bioassays of bovine spongiform encephalopathy prions in the enzyme proceeded using knock-in mice expressing bovine prion protein. These assays could detect contaminating prions at a dilution of 1 × 10(4). After inactivating its collagenase activity, Liberase HI was injected into the abdominal cavities of knock-in mice. Four months later, prion infectivity in Liberase HI was evaluated by immunohistochemical staining and Western blotting of spleen homogenates using anti-prion protein antibodies. Western blotting and immunohistochemical staining did not detect prions in Liberase HI. Diffusion MRI and EEG evaluations performed by CJD specialists confirmed that none of the transplanted recipients had CJD. Three years of follow-up revealed that none of the Japanese recipients of islet transplants developed CJD. Prion bioassays showed that the Liberase HI used to isolate islets for transplantation was free of infectious TSE prions. Copyright © 2010 Elsevier Inc. All rights reserved.

Commentary on "The Cerebellar System and What it Signifies from a Biological Perspective: A Communication by Christofredo Jakob (1866-1956) Before the Society of Neurology and Psychiatry of Buenos Aires, December 1938".

PubMed

Tzouma, Anny; Margulies, Daniel S; Triarhou, Lazaros C

2016-08-01

This commentary highlights a "cerebellar classic" by a pioneer of neurobiology, Christfried Jakob. Jakob discussed the connectivity between the cerebellum and mesencephalic, diencephalic, and telencephalic structures in an evolutionary, developmental, and histophysiological perspective. He proposed three evolutionary morphofunctional stages, the archicerebellar, paleocerebellar, and neocerebellar; he attributed the reduced cerebellospinal connections in humans, compared to other primates, to the perfection of the rubrolenticular and thalamocortical systems and the intense ascending pathways to the red nucleus in exchange for the more elementary descending efferent pathways. Jakob hypothesized the convergence of cerebellar pathways in associative cortical regions, insisting on the intimate collaboration of the cerebellum with the frontal lobe. The extensive lines of communication between regions throughout the association cortex substantiate Jakob's intuition and begin to outline the mechanisms for substantial cerebellar involvement in functions beyond the purely motor domain. Atop a foundation of anatomical and phylogenetic mastery, Jakob conceived ideas that were noteworthy, timely, and have much relevance to our current thinking on cerebellar structure and function.

Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®)—Health Professional Version

Cancer.gov

Hereditary kidney cancer syndromes include von Hippel-Lindau disease, hereditary leiomyomatosis and renal cell cancer, Birt-Hogg-Dubé syndrome, and hereditary papillary renal carcinoma. Learn about the genetics, clinical manifestations, and management of these hereditary kidney cancer syndromes in this expert-reviewed summary.

Christfried Jakob's late views (1930-1949) on the psychogenetic function of the cerebral cortex and its localization: culmination of the neurophilosophical thought of a keen brain observer.

PubMed

Théodoridou, Zoë D; Triarhou, Lazaros C

2012-04-01

This article follows the culmination of the scientific thought of the neurobiologist Christfried Jakob (1866-1956) during the later part of his career, based on publications from 1930 to 1949, when he was between 64 and 83 years of age. Jakob emphasized the necessity of bridging philosophy to the biological sciences, neurobiology in particular. Thus, we consider him as one of the early protagonists in the emergence of neurophilosophy in the 20th century. The topics that occupied his mind were the foundations for a future philosophy of the brain, and the 'neurobiogenetic', 'neurodynamic', and 'neuropsychogenetic' problems in relation to how consciousness emerges. Jakob's views have many elements in common with great thinkers of philosophy and psychology, including Immanuel Kant, William James, Edmund Husserl, Henri Bergson, Jean Piaget and Willard Quine. A common denominator can also be discerned between Jakob's dynamic approach and certain aspects of cybernetics and neurophenomenology. Jakob propounded the interdisciplinarity of sciences as an indispensable tool for ultimately solving the enigma of consciousness. Copyright © 2011 Elsevier Inc. All rights reserved.

Genetics Home Reference: hereditary myopathy with early respiratory failure

MedlinePlus

... Home Health Conditions HMERF Hereditary myopathy with early respiratory failure Printable PDF Open All Close All Enable ... expand/collapse boxes. Description Hereditary myopathy with early respiratory failure ( HMERF ) is an inherited muscle disease that ...

Pes cavus and hereditary neuropathies: when a relationship should be suspected.

PubMed

Piazza, S; Ricci, G; Caldarazzo Ienco, E; Carlesi, C; Volpi, L; Siciliano, G; Mancuso, M

2010-12-01

The hereditary peripheral neuropathies are a clinically and genetically heterogeneous group of diseases of the peripheral nervous system. Foot deformities, including the common pes cavus, but also hammer toes and twisting of the ankle, are frequently present in patients with hereditary peripheral neuropathy, and often represent one of the first signs of the disease. Pes cavus in hereditary peripheral neuropathies is caused by imbalance between the intrinsic muscles of the foot and the muscles of the leg. Accurate clinical evaluation in patients with pes cavus is necessary to exclude or confirm the presence of peripheral neuropathy. Hereditary peripheral neuropathies should be suspected in those cases with bilateral foot deformities, in the presence of family history for pes cavus and/or gait impairment, and in the presence of neurological symptoms or signs, such as distal muscle hypotrophy of limbs. Herein, we review the hereditary peripheral neuropathies in which pes cavus plays a key role as a "spy sign," discussing the clinical and molecular features of these disorders to highlight the importance of pes cavus as a helpful clinical sign in these rare diseases.

Hereditary angioedema: a bradykinin-mediated swelling disorder.

PubMed

Björkqvist, Jenny; Sala-Cunill, Anna; Renné, Thomas

2013-03-01

Edema is tissue swelling and is a common symptom in a variety of diseases. Edema form due to accumulation of fluids, either through reduced drainage or increased vascular permeability. There are multiple vascular signalling pathways that regulate vessel permeability. An important mediator that increases vascular leak is the peptide hormone bradykinin, which is the principal agent in the swelling disorder hereditary angioedema. The disease is autosomal dominant inherited and presents clinically with recurrent episodes of acute swelling that can be life-threatening involving the skin, the oropharyngeal, laryngeal, and gastrointestinal mucosa. Three different types of hereditary angiodema exist in patients. The review summarises current knowledge on the pathophysiology of hereditary angiodema and focuses on recent experimental and pharmacological findings that have led to a better understanding and new treatments for the disease.

Hereditary chronic pancreatitis: implications for surgical treatment and follow-up.

PubMed

Cowles, R A; Eckhauser, F E; Knol, J A

2001-02-01

Hereditary pancreatitis is an uncommon cause of chronic pancreatitis in Western society. It should be suspected when chronic pancreatitis presents in young adults. The diagnosis is made when chronic pancreatitis is present in several members of the same family who are determined not to have other risk factors for chronic pancreatitis. Molecular research focusing on mutations in the trypsinogen gene has uncovered the genetic defects associated with hereditary pancreatitis, and this knowledge has suggested the possible pathophysiologic mechanism of this disease. Because patients with hereditary pancreatitis develop their disease early in life they are very likely to require treatment for complications. As in patients with chronic pancreatitis of other etiologies those with hereditary pancreatitis should be treated medically for acute exacerbations. When complications occur or when the disease causes intractable pain surgery is recommended. Surgical therapy is tailored to the patient's pancreatic anatomy based on endoscopic retrograde cholangiopancreatography or CT scan. The two patients described in this report underwent successful longitudinal pancreaticojejunostomy (Puestow procedure) with good results. Finally it has been shown that patients with hereditary pancreatitis are at increased risk for developing pancreatic adenocarcinoma. Although not widely used pancreatic cancer screening programs have been suggested for surveillance of these patients.

Genetics Home Reference: Leber hereditary optic neuropathy

MedlinePlus

... What is the prognosis of a genetic condition? Genetic and Rare Diseases Information Center Frequency The prevalence of LHON in ... Nerve Disorders Health Topic: Vision Impairment and Blindness Genetic and Rare Diseases Information Center (1 link) Leber hereditary optic neuropathy ...

Christfried Jakob's Late Views (1930-1949) on the Psychogenetic Function of the Cerebral Cortex and Its Localization: Culmination of the Neurophilosophical Thought of a Keen Brain Observer

ERIC Educational Resources Information Center

Theodoridou, Zoe D.; Triarhou, Lazaros C.

2012-01-01

This article follows the culmination of the scientific thought of the neurobiologist Christfried Jakob (1866-1956) during the later part of his career, based on publications from 1930 to 1949, when he was between 64 and 83 years of age. Jakob emphasized the necessity of bridging philosophy to the biological sciences, neurobiology in particular.…

Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®)—Health Professional Version

Cancer.gov

Genetics of Kidney Cancer (Renal Cell) includes the hereditary cancer syndromes von Hippel-Lindau disease, hereditary leiomyomatosis and renal cell cancer, Birt-Hogg-Dubé syndrome, and hereditary papillary renal carcinoma. Get comprehensive information on these syndromes in this clinician summary.

Epidemiology of hereditary ocular disorders.

PubMed

Rosenberg, Thomas

2003-01-01

Molecular genetic evidence has contributed significantly to the understanding of the fundamental molecular biology of the eye in health and disease, but it has also exposed the inadequacy of our traditional clinically based classification of hereditary eye disorders by unravelling significant genetic non-allelic heterogeneity in many eye disorders. Furthermore, our understanding of the epidemiology of hereditary ocular disorders has gained considerably by the establishment of mutation spectra in a rapidly growing number of monogenic eye disorders. In this overview, special emphasis has been put on the growing impact of genetic eye diseases in visual impairment, genetic heterogeneity, and the role of founder mutations for the skewed appearance of certain hereditary ocular disorders in some populations.

Is mad cow disease caused by a bacteria?

PubMed

Broxmeyer, L

2004-01-01

Transmissible spongioform enchephalopathies (TSE's), include bovine spongiform encephalopathy (also called BSE or "mad cow disease"), Creutzfeldt-Jakob disease (CJD) in humans, and scrapie in sheep. They remain a mystery, their cause hotly debated. But between 1994 and 1996, 12 people in England came down with CJD, the human form of mad cow, and all had eaten beef from suspect cows. Current mad cow diagnosis lies solely in the detection of late appearing "prions", an acronym for hypothesized, gene-less, misfolded proteins, somehow claimed to cause the disease. Yet laboratory preparations of prions contain other things, which could include unidentified bacteria or viruses. Furthermore, the rigors of prion purification alone, might, in and of themselves, have killed the causative virus or bacteria. Therefore, even if samples appear to infect animals, it is impossible to prove that prions are causative. Manuelidis found viral-like particles, which even when separated from prions, were responsible for spongiform STE's. Subsequently, Lasmezas's study showed that 55% of mice injected with cattle BSE, and who came down with disease, had no detectable prions. Still, incredibly, prions, are held as existing TSE dogma and Heino Dringer, who did pioneer work on their nature, candidly predicts "it will turn out that the prion concept is wrong." Many animals that die of spongiform TSE's never show evidence of misfolded proteins, and Dr. Frank Bastian, of Tulane, an authority, thinks the disorder is caused by the bacterial DNA he found in this group of diseases. Recently, Roels and Walravens isolated Mycobacterium bovis it from the brain of a cow with the clinical and histopathological signs of mad cow. Moreover, epidemiologic maps of the origins and peak incidence of BSE in the UK, suggestively match those of England's areas of highest bovine tuberculosis, the Southwest, where Britain's mad cow epidemic began. The neurotoxic potential for cow tuberculosis was shown in pre-1960 England, where one quarter of all tuberculous meningitis victims suffered from Mycobacterium bovis infection. And Harley's study showed pathology identical to "mad cow" from systemic M. bovis in cattle, causing a tuberculous spongiform encephalitis. In addition to M. bovis, Mycobacterium avium subspecies paratuberculosis (fowl tuberculosis) causes Johne's disease, a problem known and neglected in cattle and sheep for almost a century, and rapidly emerging as the disease of the new millennium. Not only has M. paratuberculosis been found in human Crohn's disease, but both Crohn's and Johne's both cross-react with the antigens of cattle paratuberculosis. Furthermore, central neurologic manifestations of Crohn's disease are not unknown. There is no known disease which better fits into what is occurring in Mad Cow and the spongiform enchephalopathies than bovine tuberculosis and its blood-brain barrier penetrating, virus-like, cell-wall-deficient forms. It is for these reasons that future research needs to be aimed in this direction. Copyright 2004 Elsevier Ltd.

Rickets in Denmark.

PubMed

Beck-Nielsen, Signe Sparre

2012-02-01

Rickets is a heterogeneous group of diseases of the growing child caused by defect mineralization of bone. Nutritional rickets is caused by deficiency of vitamin D, calcium or both. Several hereditary forms of rickets exist where the disease proceeds into adulthood. Nutritional rickets was common in the past, but by introduction of preventative administration of cod liver oil and vitamin D supplementation, nutritional rickets became a rarity. During the last decades, case reports of nutritional rickets reappear in the industrialized countries. It is the general conception that in the industrialized countries, hereditary rickets is the most prevalent cause of rickets today. However, the incidence of nutritional rickets and the incidence and prevalence of hereditary rickets in Scandinavia are unknown. The most common form of hereditary rickets is hypophosphatemic rickets (HR). The geno- and phenotype among Scandinavian patients have not been characterized. Especially, the disease in adult patients is not well described. Moreover, there are conflicting reports of the benefits of medical treatment throughout childhood, and in addition on gender differences in disease severity.

Jakob Narkiewicz-Jodko-Tesla ``Predecessor''

NASA Astrophysics Data System (ADS)

Samuilov, Vladimir; Kiselev, Vladimir

2014-03-01

Prof. Jakob Narkiewicz-Jodko (1947-1905) is a bright figure in the history of science of the XIXth century. His major discoveries are: Electrography - the method of the visualization of electric discharge from the bodies due to the application of high strength and high frequency electric fields, and one of the first observations of the propagation of the electromagnetic waives and information transfer over the distances. We review Prof. Jakob Narkiewicz-Jodko's research results and explain our point why we consider him as the predecessor of Nikola Tesla.

Hereditary medullary thyroid carcinoma: the management dilemma.

PubMed

Zhou, Ping; Liu, Jian; Cheng, Shao-Wen; Wang, Bing; Yang, Rong; Peng, Ling

2012-06-01

Hereditary medullary thyroid carcinoma (hereditary MTC) is a rare malignancy, accounting for 25-30% of all MTC. It occurs as part of multiple endocrine neoplasia type 2 (MEN 2). Autosomal dominant gain-of-function mutations in the RET proto-oncogene is the cause of the disease, in which the common mutations are codons 609, 611, 618, 620, 630, 634 and 918. In recent years, the spectrum of RET gene mutations has changed. The classical mutations reduced, whereas the less aggressive mutations increased. Hereditary MTC is a time-dependent disease. Stages of the disorder at diagnosis can significantly influence survival rates. Based on the genotype-phenotype, RET mutations have been classified into four risk levels by American Thyroid Association (ATA) at 2009. The classification system guides the hereditary MTC management, including risk assessment, biochemical screenings and surgical intervention. Though the application of genetic testing and codon-specific phenotypes in hereditary MTC diagnosis is effective with high accuracy, there are some difficulties in implementing RET gene testing as a routine for MTC diagnosis. And most of carriers with RET mutations did not undergo thyroidectomy at the age recommended by the ATA guidelines. The aim of the study is to review the hereditary MTC and discuss the management dilemma.

Confronting "hereditary" disease: eugenic attempts to eliminate tuberculosis in progressive era America.

PubMed

Wilson, Philip K

2006-01-01

Tuberculosis was clearly one of the most predominant diseases of the early twentieth century. At this time, Americans involved in the eugenics movement grew increasingly interested in methods to prevent this disease's potential hereditary spread. To do so, as this essay examines, eugenicists' attempted to shift the accepted view that tuberculosis arose from infection and contagion to a view of its heritable nature. The methods that they employed to better understand the propagation and control of tuberculosis are also discussed. Finally, the essay explores the interpretative analyses of data that the Eugenics Record Office used in an attempt to convince contemporaries of the hereditary transmission of tuberculosis.

[Leber's hereditary optic neuropathy].

PubMed

Hilo, Wasseem; Jabaly-Habib, Haneen; Modi, Naftali; Briscoe, Daniel

2013-08-01

Lebers hereditary optic neuropathy (LHON) is a maternally inherited disease characterized by subacute severe visual loss in both eyes, which usually manifests in young adulthood. The disease has maternal inheritance due to mitochondrial DNA mutation. The final diagnosis is genetic. There is still no proven treatment, but there is significant progress in developments on the genetics of the disease to reach gene therapy. In this article we review the latest literature relevant to this disease.

Distribution of immunodeficiency fact files with XML--from Web to WAP.

PubMed

Väliaho, Jouni; Riikonen, Pentti; Vihinen, Mauno

2005-06-26

Although biomedical information is growing rapidly, it is difficult to find and retrieve validated data especially for rare hereditary diseases. There is an increased need for services capable of integrating and validating information as well as proving it in a logically organized structure. A XML-based language enables creation of open source databases for storage, maintenance and delivery for different platforms. Here we present a new data model called fact file and an XML-based specification Inherited Disease Markup Language (IDML), that were developed to facilitate disease information integration, storage and exchange. The data model was applied to primary immunodeficiencies, but it can be used for any hereditary disease. Fact files integrate biomedical, genetic and clinical information related to hereditary diseases. IDML and fact files were used to build a comprehensive Web and WAP accessible knowledge base ImmunoDeficiency Resource (IDR) available at http://bioinf.uta.fi/idr/. A fact file is a user oriented user interface, which serves as a starting point to explore information on hereditary diseases. The IDML enables the seamless integration and presentation of genetic and disease information resources in the Internet. IDML can be used to build information services for all kinds of inherited diseases. The open source specification and related programs are available at http://bioinf.uta.fi/idml/.

[Hereditary angioedema: a therapeutic revolution].

PubMed

Bouillet, L

2012-03-01

Hereditary angioedema is a rare disease, often diagnosed with delay because of a heterogeneous clinical presentation. Before diagnosis, patients frequently present subcutaneous edema or abdominal pains during many years. Laryngeal edema can be life-threatening. Hereditary angioedema may impair the quality of life of the patients and their social and professional life. It is important that the physicians recognize and treat the disease as soon as possible after the first attacks. Since the past five years, new drugs developed for hereditary angioedema have changed dramatically the outcome of this disorder. The objective of this review is to detail the new therapeutic guidelines. Copyright © 2012 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

Hereditary hemochromatosis, iron, hepcidin, and coronary heart disease.

PubMed

Mascitelli, Luca; Goldstein, Mark R

2014-03-01

Mounting evidence suggests that a state of sustained iron depletion may exert a primary protective action against coronary heart disease. A persistent criticism of the iron hypothesis has been that atherosclerosis may not be a prominent feature of hereditary hemochromatosis. The essence of this criticism is that iron cannot be a significant factor in atherogenesis in those unaffected by inherited iron overload unless an increase in atherosclerosis is observed in hereditary hemochromatosis. However, the emerging details of the physiology of hepcidin, the key hormone in iron recycling, suggest a resolution of the apparent paradox of an important role for iron in atherogenesis in the possible absence of increased plaque burden in most types of hereditary hemochromatosis. Copyright © 2013 Elsevier Ltd. All rights reserved.

The establishment and utility of Sweha-Reg: a Swedish population-based registry to understand hereditary angioedema

PubMed Central

Mallbris, Lotus; Nordenfelt, Patrik; Björkander, Janne; Lindfors, Anders; Werner, Sonja; Wahlgren, Carl-Fredrik

2007-01-01

Background The importance of acquiring comprehensive epidemiological and clinical data on hereditary angioedema has increasingly caught the attention of physicians and scientists around the world. The development of networks and creation of comprehensive policies to improve care of people suffering from rare diseases, such as hereditary angioedema, is a stated top priority of the European Union. Hereditary angioedema is a rare disease, that it may be life-threatening. Although the exact prevalence is unknown, current estimates suggest that it is 1/10,000–1/150,000 individuals. The low prevalence requires combined efforts to gain accurate epidemiological data on the disease and so give us tools to reduce morbidity and mortality, and improve quality of life of sufferers. Methods Sweha-Reg is a population-based registry of hereditary angioedema in Sweden with the objectives of providing epidemiological data, and so creates a framework for the study of this disease. The registry contains individual-based data on diagnoses, treatments and outcomes. Conclusion The present manuscript seeks to raise awareness of the existence of Sweha-Reg to stimulate the international collaboration of registries. A synthesis of data from similar registries across several countries is required to approach an inclusive course understanding of HAE. PMID:18053127

Leigh-like encephalopathy complicating Leber's hereditary optic neuropathy.

PubMed

Funalot, Benoît; Reynier, Pascal; Vighetto, Alain; Ranoux, Danièle; Bonnefont, Jean-Paul; Godinot, Catherine; Malthièry, Yves; Mas, Jean-Louis

2002-09-01

Leber's hereditary optic neuropathy is a mitochondrial disease caused by point mutations in mitochondrial DNA. It usually presents as severe bilateral visual loss in young adults. We report on a neurological disorder resembling Leigh syndrome, which complicated Leber's hereditary optic neuropathy in three unrelated male patients harboring mitochondrial DNA mutations at nucleotide positions 3460, 14459, and 14484, respectively. This Leigh-like encephalopathy appears to be associated with a much more severe outcome than isolated Leber's hereditary optic neuropathy.

The kuru infectious agent is a unique geographic isolate distinct from Creutzfeldt–Jakob disease and scrapie agents

PubMed Central

Manuelidis, Laura; Chakrabarty, Trisha; Miyazawa, Kohtaro; Nduom, Nana-Aba; Emmerling, Kaitlin

2009-01-01

Human sporadic Creutzfeldt–Jakob disease (sCJD), endemic sheep scrapie, and epidemic bovine spongiform encephalopathy (BSE) are caused by a related group of infectious agents. The new U.K. BSE agent spread to many species, including humans, and clarifying the origin, specificity, virulence, and diversity of these agents is critical, particularly because infected humans do not develop disease for many years. As with viruses, transmissible spongiform encephalopathy (TSE) agents can adapt to new species and become more virulent yet maintain fundamentally unique and stable identities. To make agent differences manifest, one must keep the host genotype constant. Many TSE agents have revealed their independent identities in normal mice. We transmitted primate kuru, a TSE once epidemic in New Guinea, to mice expressing normal and ≈8-fold higher levels of murine prion protein (PrP). High levels of murine PrP did not prevent infection but instead shortened incubation time, as would be expected for a viral receptor. Sporadic CJD and BSE agents and representative scrapie agents were clearly different from kuru in incubation time, brain neuropathology, and lymphoreticular involvement. Many TSE agents can infect monotypic cultured GT1 cells, and unlike sporadic CJD isolates, kuru rapidly and stably infected these cells. The geographic independence of the kuru agent provides additional reasons to explore causal environmental pathogens in these infectious neurodegenerative diseases. PMID:19633190

Hereditary Angioedema: The Economics of Treatment of an Orphan Disease.

PubMed

Lumry, William Raymond

2018-01-01

This review will discuss the cost burden of hereditary angioedema on patients, healthcare systems, and society. The impact of availability of and access to novel and specific therapies on morbidity, mortality, and the overall burden of disease will be explored along with potential changes in treatment paradigms to improve effectiveness and reduce cost of treatment. The prevalence of orphan diseases, legislative incentives to encourage development of orphan disease therapies and the impact of orphan disease treatment on healthcare payment systems will be discussed.

[Paediatric retinal detachment and hereditary vitreoretinal disorders].

PubMed

Meier, P

2013-09-01

The number of retinal detachments in children is very low in comparison to the number in adults. One predisposing factor for development of paediatric retinal detachment is suffering from hereditary vitreoretinal degeneration (e.g., Stickler syndrome, Wagner syndrome, Kniest dysplasia, familial exudative vitreoretinopathy, congenital X-linked retinoschisis, Knobloch syndrome, incontinentia pigmenti, Norrie disease). Hereditary vitreoretinopathies are characterised by an abnormal-appearing vitreous gel with associated retinal changes. In most of these eyes further ocular abnormalities can be diagnosed. A group of hereditary disorders is associated with characteristic systemic abnormalities. Allied conditions should be considered in the clinical diagnosis. Vitreoretinopathies are the most common cause of inherited retinal detachment. In most eyes primary vitrectomy is necessary, and disease-specific surgical treatment is discussed. Georg Thieme Verlag KG Stuttgart · New York.

Removal of transmissible spongiform encephalopathy prion from large volumes of cell culture media supplemented with fetal bovine serum by using hollow fiber anion-exchange membrane chromatography.

PubMed

Chou, Ming Li; Bailey, Andy; Avory, Tiffany; Tanimoto, Junji; Burnouf, Thierry

2015-01-01

Cases of variant Creutzfeldt-Jakob disease in people who had consumed contaminated meat products from cattle with bovine spongiform encephalopathy emphasize the need for measures aimed at preventing the transmission of the pathogenic prion protein (PrPSc) from materials derived from cattle. Highly stringent scrutiny is required for fetal bovine serum (FBS), a growth-medium supplement used in the production of parenteral vaccines and therapeutic recombinant proteins and in the ex vivo expansion of stem cells for transplantation. One such approach is the implementation of manufacturing steps dedicated to removing PrPSc from materials containing FBS. We evaluated the use of the QyuSpeed D (QSD) adsorbent hollow-fiber anion-exchange chromatographic column (Asahi Kasei Medical, Tokyo, Japan) for the removal of PrPSc from cell culture media supplemented with FBS. We first established that QSD filtration had no adverse effect on the chemical composition of various types of culture media supplemented with 10% FBS or the growth and viability characteristics of human embryonic kidney (HEK293) cells, baby hamster kidney (BHK-21) cells, African green monkey kidney (Vero) cells, and Chinese hamster ovary (CHO-k1) cells propagated in the various culture-medium filtrates. We used a 0.6-mL QSD column for removing PrPSc from up to 1000 mL of Dulbecco's modified Eagle's medium containing 10% FBS previously spiked with the 263K strain of hamster-adapted scrapie. The Western blot analysis, validated alongside an infectivity assay, revealed that the level of PrPSc in the initial 200mL flow-through was reduced by 2.5 to > 3 log10, compared with that of the starting material. These results indicate that QSD filtration removes PrPSc from cell culture media containing 10% FBS, and demonstrate the ease with which QSD filtration can be implemented in at industrial-scale to improve the safety of vaccines, therapeutic recombinant proteins, and ex vivo expanded stem cells produced using growth media supplemented with FBS.

Removal of Transmissible Spongiform Encephalopathy Prion from Large Volumes of Cell Culture Media Supplemented with Fetal Bovine Serum by Using Hollow Fiber Anion-Exchange Membrane Chromatography

PubMed Central

Chou, Ming Li; Bailey, Andy; Avory, Tiffany; Tanimoto, Junji; Burnouf, Thierry

2015-01-01

Cases of variant Creutzfeldt-Jakob disease in people who had consumed contaminated meat products from cattle with bovine spongiform encephalopathy emphasize the need for measures aimed at preventing the transmission of the pathogenic prion protein (PrPSc) from materials derived from cattle. Highly stringent scrutiny is required for fetal bovine serum (FBS), a growth-medium supplement used in the production of parenteral vaccines and therapeutic recombinant proteins and in the ex vivo expansion of stem cells for transplantation. One such approach is the implementation of manufacturing steps dedicated to removing PrPSc from materials containing FBS. We evaluated the use of the QyuSpeed D (QSD) adsorbent hollow-fiber anion-exchange chromatographic column (Asahi Kasei Medical, Tokyo, Japan) for the removal of PrPSc from cell culture media supplemented with FBS. We first established that QSD filtration had no adverse effect on the chemical composition of various types of culture media supplemented with 10% FBS or the growth and viability characteristics of human embryonic kidney (HEK293) cells, baby hamster kidney (BHK-21) cells, African green monkey kidney (Vero) cells, and Chinese hamster ovary (CHO-k1) cells propagated in the various culture-medium filtrates. We used a 0.6-mL QSD column for removing PrPSc from up to 1000 mL of Dulbecco’s modified Eagle’s medium containing 10% FBS previously spiked with the 263K strain of hamster-adapted scrapie. The Western blot analysis, validated alongside an infectivity assay, revealed that the level of PrPSc in the initial 200mL flow-through was reduced by 2.5 to > 3 log10, compared with that of the starting material. These results indicate that QSD filtration removes PrPSc from cell culture media containing 10% FBS, and demonstrate the ease with which QSD filtration can be implemented in at industrial-scale to improve the safety of vaccines, therapeutic recombinant proteins, and ex vivo expanded stem cells produced using growth media supplemented with FBS. PMID:25874629

[Plasma fractionation in the world: current status].

PubMed

Burnouf, T

2007-05-01

From 22 to 25 million liters of plasma are fractionated yearly in about 70 fractionation plants, either private or government-owned, mainly located in industrialized countries, and with a capacity ranging from 50000 to three million liters. In an increasingly global environment, the plasma industry has recently gone through a major consolidation phase that has seen mergers and acquisitions, and has led to the closure of a number of small plants in Europe. Currently, some fifteen countries are involved into contract plasma fractionation programs to ensure a supply of plasma-derived medicinal products. The majority of the plasma for fractionation is obtained by automated plasmapheresis, the remaining (recovered plasma) being prepared from whole blood as a by-product of red cell production. Plasma for fractionation should be produced, and controlled following well established procedures to meet the strict quality requirements set by regulatory authorities and fractionators. The plasma fractionation technology still relies heavily on the cold ethanol fractionation process, but has been improved by the introduction of modern chromatographic purification methods, and efficient viral inactivation and removal treatments, ensuring quality and safety to a large portfolio of fractionated plasma products. The safety of these products with regards to the risk of transmission of variant Creutzfeldt-Jakob disease seems to be provided, based on current scientific data, by extensive removal of the infectious agent during certain fractionation steps. The leading plasma product is now the intravenous immunoglobulin G, which has replaced factor VIII and albumin in this role. The supply of plasma products (most specifically coagulation products and immunoglobulin) at an affordable price and in sufficient quantity remains an issue; the problem is particularly acute in developing countries, as the switch to recombinant factor VIII in rich countries has not solved the supply issue and has even led to an increase of the mean price of plasma-derived factor VIII to the developing world. In the last few years, the plasma fractionation industry has improved greatly, and should remain essential in the years to come for the procurement of many essential medicines.

Hereditary myopathies with early respiratory insufficiency in adults.

PubMed

Naddaf, Elie; Milone, Margherita

2017-11-01

Hereditary myopathies with early respiratory insufficiency as a predominant feature of the clinical phenotype are uncommon and underestimated in adults. We reviewed the clinical and laboratory data of patients with hereditary myopathies who demonstrated early respiratory insufficiency before the need for ambulatory assistance. Only patients with disease-causing mutations or a specific histopathological diagnosis were included. Patients with cardiomyopathy were excluded. We identified 22 patients; half had isolated respiratory symptoms at onset. The diagnosis of the myopathy was often delayed, resulting in delayed ventilatory support. The most common myopathies were adult-onset Pompe disease, myofibrillar myopathy, multi-minicore disease, and myotonic dystrophy type 1. Single cases of laminopathy, MELAS (mitochondrial encephalomyopathy with lactic acidosis and strokelike events), centronuclear myopathy, and cytoplasmic body myopathy were identified. We highlighted the most common hereditary myopathies associated with early respiratory insufficiency as the predominant clinical feature, and underscored the importance of a timely diagnosis for patient care. Muscle Nerve 56: 881-886, 2017. © 2017 Wiley Periodicals, Inc.

A family with autosomal dominant mutilating neuropathy not linked to either Charcot-Marie-Tooth disease type 2B (CMT2B) or hereditary sensory neuropathy type I (HSN I) loci.

PubMed

Bellone, Emilia; Rodolico, Carmelo; Toscano, Antonio; Di Maria, Emilio; Cassandrini, Denise; Pizzuti, Antonio; Pigullo, Simona; Mazzeo, Anna; Macaione, Vincenzo; Girlanda, Paolo; Vita, Giuseppe; Ajmar, Franco; Mandich, Paola

2002-03-01

Sensory loss and ulcero-mutilating features have been observed in hereditary sensory neuropathy type I and in hereditary motor and sensory neuropathy type IIB, also referred as Charcot-Marie-Tooth disease type 2B. To date two loci associated with ulcero-mutilating neuropathy have been described: CMT2B at 3q13-q22 and HSN I at 9q22.1-q22.3. We performed linkage analysis with chromosomal markers representing the hereditary sensory neuropathy type I and Charcot-Marie-Tooth disease type 2B loci on an Italian family with a severe distal sensory loss leading to an ulcero-mutilating peripheral neuropathy. Negative likelihood-of-odds scores excluded any evidence of linkage to both chromosome 3q13 and chromosome 9q22 markers, confirming the genetic heterogeneity of this clinical entity and the presence of a third locus responsible for ulcero-mutilating neuropathies.

Exome sequencing establishes a gelsolin mutation as the cause of inherited bulbar-onset neuropathy.

PubMed

Caress, James B; Johnson, Janel O; Abramzon, Yevgeniya A; Hawkins, Gregory A; Gibbs, J Raphael; Sullivan, Elizabeth A; Chahal, Chamanpreet S; Traynor, Bryan J

2017-11-01

Progressive bulbar motor neuropathy is primarily caused by bulbar-onset ALS. Hereditary amyloidosis type IV also presents with a bulbar neuropathy that mimics motor neuron disease. The disease is prevalent in Finland only and is not commonly included in the differential diagnosis of ALS. We studied 18 members of a family in which some had bulbar motor neuropathy, and we performed exome sequencing. Five affected family members were found to have a D187Y substitution in the GSN gene known to cause hereditary amyloidosis type IV. This American family presented with progressive bulbar neuropathy due to a gelsolin mutation not found in Finland. Hereditary amyloidosis type IV presents with bulbar motor neuropathy and not with peripheral neuropathy as occurs with common forms of amyloidosis. This report demonstrates the power of exome sequencing to determine the cause of rare hereditary diseases with incomplete or atypical phenotypes. Muscle Nerve 56: 1001-1005, 2017. © 2016 Wiley Periodicals, Inc.

Hereditary Hemochromatosis (For Parents)

MedlinePlus

... buildup can be prevented. Doctors usually diagnose iron overload with these blood tests: serum ferritin : measures the ... has the disease. Treatment Doctors treat the iron overload from hereditary hemochromatosis by regularly drawing blood to ...

Rate of displacement for Jakob Type 1 lateral condyle fractures treated with a cast.

PubMed

Zale, C; Winthrop, Z A; Hennrikus, W

2018-04-01

The aim of this retrospective study is to report the rate of displacement of Jakob Type 1 lateral condyle fractures that were initially treated in a cast. We performed a retrospective review of all patients that were treated for a non-displaced (Jakob Type 1 < 2 mm) lateral condyle fracture of the humerus at our institution between 2002 and 2015. A total of 59 patients were initially treated with casting. Five fractures displaced and were converted to a closed pinning treatment plan with a conversion rate of 8.5%. There was a mean of 13.2 days (4 to 21) between treatment by initial casting and closed pinning. This study demonstrates an 8.5% displacement and conversion rate from cast treatment to closed pinning for initially non-displaced Jakob Type 1 lateral condyle fractures of the humerus. The internal oblique radiograph is most accurate to determine displacement. We recommend obtaining an internal oblique view at initial evaluation and at follow-up in the cast for lateral condyle fractures. To minimize movement at the fracture site, we recommend treating Jakob Type 1 lateral condyle fractures with a long arm cast with the elbow at 90° and the forearm in the supine position with a sling-loop design. IV - retrospective therapeutic study.

Cholesterol in brain disease: sometimes determinant and frequently implicated

PubMed Central

Martín, Mauricio G; Pfrieger, Frank; Dotti, Carlos G

2014-01-01

Cholesterol is essential for neuronal physiology, both during development and in the adult life: as a major component of cell membranes and precursor of steroid hormones, it contributes to the regulation of ion permeability, cell shape, cell–cell interaction, and transmembrane signaling. Consistently, hereditary diseases with mutations in cholesterol-related genes result in impaired brain function during early life. In addition, defects in brain cholesterol metabolism may contribute to neurological syndromes, such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD), and even to the cognitive deficits typical of the old age. In these cases, brain cholesterol defects may be secondary to disease-causing elements and contribute to the functional deficits by altering synaptic functions. In the first part of this review, we will describe hereditary and non-hereditary causes of cholesterol dyshomeostasis and the relationship to brain diseases. In the second part, we will focus on the mechanisms by which perturbation of cholesterol metabolism can affect synaptic function. PMID:25223281

[Hereditary hypophosphatemia in adults].

PubMed

Vélayoudom-Céphise, F-L; Vantyghem, M-C; Wémeau, J-L

2005-12-17

Hereditary hypophosphatemic rickets groups together X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets (ADHR) and hereditary hypophosphatemic rickets with hypercalciuria (HHRH, autosomal recessive). Clinical and biological characteristics and treatment depend on specific etiology. Mutations causing hereditary hypophosphatemic rickets involve PHEX located on Xp11.22 for XLH and FGF-23 located on 12p13 for ADHR. The gene involved in HHRH remains unknown: candidates may encode proteins that modulate phosphate transporter expression or activity. Others forms of rickets must be ruled out: acquired hypophosphatemia due to oncogenic osteomalacia, X-linked recessive hypophosphatemic rickets or Dent's disease, and hereditary 1, 25-dihydroxyvitamin D-resistant rickets with a defect either in the 1-alpha-hydroxylase gene (pseudo-vitamin D deficiency rickets, PDDR) or in the vitamin D receptor (hereditary vitamin D-resistant rickets, HVDRR).

Is Increased Intracellular Calcium in Red Blood Cells a Common Component in the Molecular Mechanism Causing Anemia?

PubMed Central

Hertz, Laura; Huisjes, Rick; Llaudet-Planas, Esther; Petkova-Kirova, Polina; Makhro, Asya; Danielczok, Jens G.; Egee, Stephane; del Mar Mañú-Pereira, Maria; van Wijk, Richard; Vives Corrons, Joan-Lluis; Bogdanova, Anna; Kaestner, Lars

2017-01-01

For many hereditary disorders, although the underlying genetic mutation may be known, the molecular mechanism leading to hemolytic anemia is still unclear and needs further investigation. Previous studies revealed an increased intracellular Ca2+ in red blood cells (RBCs) from patients with sickle cell disease, thalassemia, or Gardos channelopathy. Therefore we analyzed RBCs' Ca2+ content from 35 patients with different types of anemia (16 patients with hereditary spherocytosis, 11 patients with hereditary xerocytosis, 5 patients with enzymopathies, and 3 patients with hemolytic anemia of unknown cause). Intracellular Ca2+ in RBCs was measured by fluorescence microscopy using the fluorescent Ca2+ indicator Fluo-4 and subsequent single cell analysis. We found that in RBCs from patients with hereditary spherocytosis and hereditary xerocytosis the intracellular Ca2+ levels were significantly increased compared to healthy control samples. For enzymopathies and hemolytic anemia of unknown cause the intracellular Ca2+ levels in RBCs were not significantly different. These results lead us to the hypothesis that increased Ca2+ levels in RBCs are a shared component in the mechanism causing an accelerated clearance of RBCs from the blood stream in channelopathies such as hereditary xerocytosis and in diseases involving defects of cytoskeletal components like hereditary spherocytosis. Future drug developments should benefit from targeting Ca2+ entry mediating molecular players leading to better therapies for patients. PMID:28932200

Molecular dynamics studies on the buffalo prion protein.

PubMed

Zhang, Jiapu; Wang, Feng; Chatterjee, Subhojyoti

2016-01-01

It was reported that buffalo is a low susceptibility species resisting to transmissible spongiform encephalopathies (TSEs) (same as rabbits, horses, and dogs). TSEs, also called prion diseases, are invariably fatal and highly infectious neurodegenerative diseases that affect a wide variety of species (except for rabbits, dogs, horses, and buffalo), manifesting as scrapie in sheep and goats; bovine spongiform encephalopathy (BSE or "mad-cow" disease) in cattle; chronic wasting disease in deer and elk; and Creutzfeldt-Jakob diseases, Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia, and Kulu in humans etc. In molecular structures, these neurodegenerative diseases are caused by the conversion from a soluble normal cellular prion protein (PrP(C)), predominantly with α-helices, into insoluble abnormally folded infectious prions (PrP(Sc)), rich in β-sheets. In this article, we studied the molecular structure and structural dynamics of buffalo PrP(C) (BufPrP(C)), in order to understand the reason why buffalo is resistant to prion diseases. We first did molecular modeling of a homology structure constructed by one mutation at residue 143 from the NMR structure of bovine and cattle PrP(124-227); immediately we found that for BufPrP(C)(124-227), there are five hydrogen bonds (HBs) at Asn143, but at this position, bovine/cattle do not have such HBs. Same as that of rabbits, dogs, or horses, our molecular dynamics studies also revealed there is a strong salt bridge (SB) ASP178-ARG164 (O-N) keeping the β2-α2 loop linked in buffalo. We also found there is a very strong HB SER170-TYR218 linking this loop with the C-terminal end of α-helix H3. Other information, such as (i) there is a very strong SB HIS187-ARG156 (N-O) linking α-helices H2 and H1 (if mutation H187R is made at position 187, then the hydrophobic core of PrP(C) will be exposed (L.H. Zhong (2010). Exposure of hydrophobic core in human prion protein pathogenic mutant H187R. Journal of Biomolecular Structure and Dynamics 28(3), 355-361)), (ii) at D178, there is a HB Y169-D178 and a polar contact R164-D178 for BufPrP(C) instead of a polar contact Q168-D178 for bovine PrP(C) (C.J. Cheng, & V. Daggett. (2014). Molecular dynamics simulations capture the misfolding of the bovine prion protein at acidic pH. Biomolecules 4(1), 181-201), (iii) BufPrP(C) owns three 310 helices at 125-127, 152-156, and in the β2-α2 loop, respectively, and (iv) in the β2-α2 loop, there is a strong π-π stacking and a strong π-cation F175-Y169-R164.(N)NH2, has been discovered.

[Hereditary gastric and pancreatic cancer predisposition syndromes].

PubMed

Leoz, María Liz; Sánchez, Ariadna; Carballal, Sabela; Ruano, Lucía; Ocaña, Teresa; Pellisé, María; Castells, Antoni; Balaguer, Francesc; Moreira, Leticia

2016-01-01

The most common hereditary gastrointestinal cancers are colorectal, mainly hereditary nonpolyposis colorectal cancer (Lynch syndrome) and familial adenomatous polyposis. Other extracolonic neoplasms, including the gastric and pancreatic adenocarcinomas, are less well known and studied because they account for a relatively small percentage of hereditary gastrointestinal cancers. Nonetheless, they merit special attention because of the high associated morbidity and mortality rates. We review the hereditary and familial syndromes associated with gastric and pancreatic cancers with a view to improving knowledge and understanding of these diseases, in order to heighten diagnostic suspicion and thus implement appropriate diagnostic strategies, screening, surveillance and treatment. Copyright © 2016 Elsevier España, S.L.U. y AEEH y AEG. All rights reserved.

Causes of childhood blindness in a developing country and an underdeveloped country.

PubMed

Santos-Bueso, E; Dorronzoro-Ramírez, E; Gegúndez-Fernández, J A; Vinuesa-Silva, J M; Vinuesa-Silva, I; García-Sánchez, J

2015-05-01

The causes of childhood blindness depend on factors such as geographic location or the human development index of the populations under study. The main causes in developed countries are genetic and hereditary diseases, while infectious and contagious diseases, together with nutritional and vitamin deficiencies, are the main causes in underdeveloped countries (UDCs). Study of the causes of blindness among children admitted to a regional centre in Nador, Morocco, and among children in Mekele, Ethiopia. The study was carried out in collaboration with two non-governmental organizations based in Madrid, Spain. First, we worked with Fudación Adelias in June 2010, and with Proyecto Visión in October 2012. The study comprised a total of 27 children in Morocco and 85 in Ethiopia. The average age of the children was 10.92 and 6.94 years, respectively. The main causes of blindness in Morocco were hereditary pathologies (25.92%) and refractive errors (14.82%), although trauma (7.40%) and corneal disease (7.40%) are relevant. Among the children from Ethiopia, corneal disease (27.05%) and trauma (20%) were the main causes of blindness, while congenital and hereditary diseases had a lower prevalence (4.70%). The causes of blindness depend on the human development index of the populations under study. While corneal disease and trauma are the main causes observed in UDCs like Ethiopia, hereditary pathologies and refractive errors are the main causes within the Moroccan population studied. A mixed form can be observed in this country, as the cause of blindness found in developed countries, such as congenital and hereditary pathologies which are present alongside the causes normally found in LDCs. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Hereditary and non-hereditary microangiopathies in the young. An up-date.

PubMed

Ringelstein, E Bernd; Kleffner, Ilka; Dittrich, Ralf; Kuhlenbäumer, Gregor; Ritter, Martin A

2010-12-15

In recent years, a considerable number of new sporadic or hereditary small artery diseases of the brain have been detected which preferably occur in younger age, below 45 years. Cerebral microangiopathies constitute an appreciable portion of all strokes. In middle aged patients, hereditary cerebral small vessel diseases have to be separated from sporadic degenerative cerebral microangiopathy which is mainly due to a high vascular risk load. Features of the following disorders and details how to differentiate them, are reviewed here, namely CADASIL, MELAS, AD-RVLC, HEMID, CARASIL, PADMAL, FABRY, COL4A1-related cerebral small vessel diseases and a Portuguese type of autosomal dominant cerebral small vessel disease (SVDB). The symptomatic overlap of the cerebral microangiopathies include also other distinctive non-hereditary diseases like posterior (reversible) encephalopathy and Susac's syndrome which are also described. Some of the microangiopathies described here are not only seen in the young but also in the elderly. The precise diagnosis has direct therapeutic implications in several of these entities. Cerebral microangiopathies cause recurring strokes and diffuse white matter lesions leading to a broad spectrum of gait disturbances and in most of these disorders cognitive impairment or even vascular dementia in the long term. Often, they also involve the eye, the inner ear or the kidney. Several typical imaging findings from illustrative cases are presented. The order in which these diseases are presented here is not dictated by an inner logic principle, because a genetically or pathophysiologically based classification system of all these entities does not exist yet. Some entities are well established and not unusual, whereas others have only been described in a few cases in total. Copyright © 2010 Elsevier B.V. All rights reserved.

[Clinical and genetic special features of Niemann-Pick disease, type C].

PubMed

Zakharova, E Iu; Mikhaĭlova, S V; Proshliakova, T Iu; Rudenskaia, G E

2012-01-01

Niemann-Pick disease, type C is a rare hereditary disorder of the group of lisosomal storage diseases, caused by mutations in the genes NPC1 or NPC2. Depending on the onset age, several clinical forms of this disease, which differs by manifestation age, main clinical signs and clinical course, are distinguished. Niemann-Pick disease type C can imitate other hereditary and acquired diseases, which complicates its early diagnostics. Clinical and genetic diversity of this disorder, considered on the clinical cases diagnosed at the FSI "RCMG" of RAMS, are discussed in this review.

The dog genome map and its use in mammalian comparative genomics.

PubMed

Switonski, Marek; Szczerbal, Izabela; Nowacka, Joanna

2004-01-01

The dog genome organization was extensively studied in the last ten years. The most important achievements are the well-developed marker genome maps, including over 3200 marker loci, and a survey of the DNA genome sequence. This knowledge, along with the most advanced map of the human genome, turned out to be very useful in comparative genomic studies. On the one hand, it has promoted the development of marker genome maps of other species of the family Canidae (red fox, arctic fox, Chinese raccoon dog) as well as studies on the evolution of their karyotype. But the most important approach is the comparative analysis of human and canine hereditary diseases. At present, causative gene mutations are known for 30 canine hereditary diseases. A majority of them have human counterparts with similar clinical and molecular features. Studies on identification of genes having a major impact on some multifactorial diseases (hip dysplasia, epilepsy) and cancers (multifocal renal cystadenocarcinoma and nodular dermatofibrosis) are advanced. Very promising are the results of gene therapy for certain canine monogenic diseases (haemophilia, hereditary retinal dystrophy, mucopolysaccharidosis), which have human equivalents. The above-mentioned examples prove a very important model role of the dog in studies of human genetic diseases. On the other hand, the identification of gene mutations responsible for hereditary diseases has a substantial impact on breeding strategy in the dog.

The potential of disease management for neuromuscular hereditary disorders.

PubMed

Chouinard, Maud-Christine; Gagnon, Cynthia; Laberge, Luc; Tremblay, Carmen; Côté, Charlotte; Leclerc, Nadine; Mathieu, Jean

2009-01-01

Neuromuscular hereditary disorders require long-term multidisciplinary rehabilitation management. Although the need for coordinated healthcare management has long been recognized, most neuromuscular disorders are still lacking clinical guidelines about their long-term management and structured evaluation plan with associated services. One of the most prevalent adult-onset neuromuscular disorders, myotonic dystrophy type 1, generally presents several comorbidities and a variable clinical picture, making management a constant challenge. This article presents a healthcare follow-up plan and proposes a nursing case management within a disease management program as an innovative and promising approach. This disease management program and model consists of eight components including population identification processes, evidence-based practice guidelines, collaborative practice, patient self-management education, and process outcomes evaluation (Disease Management Association of America, 2004). It is believed to have the potential to significantly improve healthcare management for neuromuscular hereditary disorders and will prove useful to nurses delivering and organizing services for this population.

Genetics of hereditary disorders of magnesium homeostasis.

PubMed

Schlingmann, Karl P; Konrad, Martin; Seyberth, Hannsjörg W

2004-01-01

Magnesium plays an essential role in many biochemical and physiological processes. Homeostasis of magnesium is tightly regulated and depends on the balance between intestinal absorption and renal excretion. During the last decades, various hereditary disorders of magnesium handling have been clinically characterized and genetic studies in affected individuals have led to the identification of some molecular components of cellular magnesium transport. In addition to these hereditary forms of magnesium deficiency, recent studies have revealed a high prevalence of latent hypomagnesemia in the general population. This finding is of special interest in view of the association between hypomagnesemia and common chronic diseases such as diabetes, coronary heart disease, hypertension, and asthma. However, valuable methods for the diagnosis of body and tissue magnesium deficiency are still lacking. This review focuses on clinical and genetic aspects of hereditary disorders of magnesium homeostasis. We will review primary defects of epithelial magnesium transport, disorders associated with defects in Ca(2+)/ Mg(2+) sensing, as well as diseases characterized by renal salt wasting and hypokalemic alkalosis, with special emphasis on disturbed magnesium homeostasis.

High-Performance 3D Image Processing Architectures for Image-Guided Interventions

DTIC Science & Technology

2008-01-01

Parallel architectures and algorithms for image understanding. Boston: Academic Press, 1991. [99] A. Bruhn, T. Jakob, M. Fischer, T. Kohlberger , J...Symposium on Pattern Recognition, vol. 2449(pp. 290-297, 2002. [100] A. Bruhn, T. Jakob, M. Fischer, T. Kohlberger , J. Weickert, U. Bruning, and C

Network for Early Onset Cystic Kidney Diseases-A Comprehensive Multidisciplinary Approach to Hereditary Cystic Kidney Diseases in Childhood.

PubMed

König, Jens Christian; Titieni, Andrea; Konrad, Martin

2018-01-01

Hereditary cystic kidney diseases comprise a complex group of genetic disorders representing one of the most common causes of end-stage renal failure in childhood. The main representatives are autosomal recessive polycystic kidney disease, nephronophthisis, Bardet-Biedl syndrome, and hepatocyte nuclear factor-1beta nephropathy. Within the last years, genetic efforts have brought tremendous progress for the molecular understanding of hereditary cystic kidney diseases identifying more than 70 genes. Yet, genetic heterogeneity, phenotypic variability, a lack of reliable genotype-phenotype correlations and the absence of disease-specific biomarkers remain major challenges for physicians treating children with cystic kidney diseases. To tackle these challenges comprehensive scientific approaches are urgently needed that match the ongoing "revolution" in genetics and molecular biology with an improved efficacy of clinical data collection. Network for early onset cystic kidney diseases (NEOCYST) is a multidisciplinary, multicenter collaborative combining a detailed collection of clinical data with translational scientific approaches addressing the genetic, molecular, and functional background of hereditary cystic kidney diseases. Consisting of seven work packages, including an international registry as well as a biobank, NEOCYST is not only dedicated to current scientific questions, but also provides a platform for longitudinal clinical surveillance and provides precious sources for high-quality research projects and future clinical trials. Funded by the German Federal Government, the NEOCYST collaborative started in February 2016. Here, we would like to introduce the rationale, design, and objectives of the network followed by a short overview on the current state of progress.

Soil humic substances hinder the propagation of prions

NASA Astrophysics Data System (ADS)

Leita, Liviana; Giachin, Gabriele; Margon, Alja; Narkiewicz, Joanna; Legname, Giuseppe

2013-04-01

Prions are infectious pathogens causing fatal neurodegenerative disorders, known as transmissible spongiform encephalopathies (TSEs), or prion diseases, which affect different mammalian species. TSEs include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in mule deer, elk, and moose (cervids), and Creutzfeldt-Jakob disease (CJD) in humans. The prominent, if not only, component of prions is a misfolded conformer (PrPSc) of a constitutive sialoglycoprotein, the cellular prion protein (PrPC). A notable feature of prion diseases is horizontal transmission between grazing animals, implying that contaminated soil may serve to propagate the disease. In this respect, it has been reported that grazing animals ingest from tens to hundreds grams of soil per day, either incidentally through the diet, or deliberately in answering salt needs, and that mule deer can develop CWD after grazing in locations that previously housed infected animals. Prions may enter the environment through different routes, including animal excreta and secreta which mainly contribute to soil contamination. Recent studies have proven that prions can be retained in soil, which could act as a carrier of infectivity even several years after the contamination. However, within the large spread of potentially infected lands, prion diseases have become endemic only in geographically limited regions. The reasons for this geographical distribution remain unknown, but it suggests a role of the different kinds of soil in either enhancing or attenuating prion infectivity. The extent of prion transmission from the contaminated environment is unknown. Several studies have tried to address the issue of prion interaction with soil, but, at the present, different approaches show several drawbacks and technical difficulties, as soil is a complex, multi-component system of both mineral and organic interacting substances. Most research has focused on the adsorption capacity of clay minerals; however the contribution of soil organic components in adsorption has so far been neglected, as they represent a minor soil fraction on a weight basis. Among organic molecules, humic substances (HSs) are natural polyanions that result among the most reactive compounds in the soil and possess the largest specific surface area. Humic substances make up a large portion of the dark matter in humus and consist of heterogeneous mixtures of transformed biomolecules exhibiting a supramolecular structure. HSs are classified as humic acids (HAs), which are soluble only in alkaline solutions, and fulvic acids (FAs), which are soluble in both alkaline and acid solutions. The amphiphilic characteristics confer to HAs and FAs great versatility to interact with xenobiotics and reasonably also with prion proteins and/or prions too, leading to the formation of adducts with peculiar chemical and biophysical characteristics, thus affecting the transport, fixation and toxicity of prion. Results from our chemical, biophysical and biochemical investigation will be presented and results on anti-prion activity exerted by HAs and FAs will be provided, thus suggesting that amendment of contaminated soil with humic substances could be a strategy to contrast prion diffusion.

Hereditary neuropathy with liability to pressure palsy: a brief review with a case report.

PubMed

Rana, Abdul Qayyum; Masroor, Mohamed Sufian

2012-03-01

Hereditary Neuropathy with Liability to Pressure Palsy (HNPP) is an autosomal dominant disorder and is usually characterized by episodes of recurrent and painless focal motor and sensory peripheral mononeuropathy. This condition is usually localized around areas of entrapment (predominantly the wrists, knees, elbows, and shoulders). The genetic locus of the disease is chromosome 17p12. A deletion of the PMP22 gene results in the lack of peripheral myelin protein, a key component to the myelin sheet of peripheral nerves. However, this disease may be completely asymptomatic until an event, such as a minor trauma, triggers these episodes, as seen in our presented case report. The diagnosis of HNPP can be somewhat challenging, as other diseases, such as Charcot-Marie-Tooth disease type 1A (CMT) and Hereditary Neuralgic Amyotrophy (HNA) must be included in the differential diagnosis due to their overlapping clinical features. There are currently no treatments to cure the disease, but therapies seek to alleviate the symptoms and recurring episodes.

Transcorneal Electrical Stimulation Therapy for Retinal Disease

ClinicalTrials.gov

2012-05-03

Retinitis Pigmentosa; Macula Off; Primary Open Angle Glaucoma; Hereditary Macular Degeneration; Treated Retina Detachment; Retinal Artery Occlusion; Retinal Vein Occlusion; Non-Arthritic-Anterior-Ischemic Optic-Neuropathy; Hereditary Autosomal Dominant Optic Atrophy; Dry Age Related Macular Degeneration; Ischemic Macula Edema

Genetics Home Reference: nonsyndromic hearing loss

MedlinePlus

... Centre for Genetics Education (Australia) Disease InfoSearch: Deafness Harvard Medical School Center for Hereditary Deafness Hereditary Hearing ... Available from http://www.ncbi.nlm.nih.gov/books/NBK1434/ Citation on ... Bulletins Genetics Home Reference Celebrates Its 15th Anniversary ...

Mitochondrial DNA Mutation Associated with Leber's Hereditary Optic Neuropathy

NASA Astrophysics Data System (ADS)

Wallace, Douglas C.; Singh, Gurparkash; Lott, Marie T.; Hodge, Judy A.; Schurr, Theodore G.; Lezza, Angela M. S.; Elsas, Louis J.; Nikoskelainen, Eeva K.

1988-12-01

Leber's hereditary optic neuropathy is a maternally inherited disease resulting in optic nerve degeneration and cardiac dysrhythmia. A mitochondrial DNA replacement mutation was identified that correlated with this disease in multiple families. This mutation converted a highly conserved arginine to a histidine at codon 340 in the NADH dehydrogenase subunit 4 gene and eliminated an Sfa NI site, thus providing a simple diagnostic test. This finding demonstrated that a nucleotide change in a mitochondrial DNA energy production gene can result in a neurological disease.

Prof. Jakob Narkiewicz-Jodko's Discoveries and his Laboratory

NASA Astrophysics Data System (ADS)

Samuilov, Vladimir; Samuilova, Larissa

2015-03-01

Prof. Jakob Narkiewicz-Jodko (1947-1905) major discoveries are: Electrography - the method of the visualization of electric discharge from the bodies due to the application of high strength and high frequency electric fields, and the first observation of the propagation of the electromagnetic waives for information transfer over the distances. They were made in his laboratory located at his manor home Nadniemen. We describe these experiments and the Lab equipment used for the discoveries. Unfortunately the Nadniemen manor designed and built in Neogothic style was destroyed at the WWII. Our goal is to restore the Lab of Prof. Jakob Narkiewicz-Jodko as a museum. We also introduce our hypothesis regarding architectural design of the manor home Nadniemen.

An avant-garde professorship of neurobiology in education: Christofredo Jakob (1866-1956) and the 1920s lead of the National University of La Plata, Argentina.

PubMed

Théodoridou, Zoe D; Koutsoklenis, Athanasios; del Cerro, Manuel; Triarhou, Lazaros C

2013-01-01

The interdisciplinary trend in "Mind, Brain, and Education" has witnessed dynamic international growth in recent years. Yet, it remains little known that the National University of La Plata in Argentina probably holds the historical precedent as the world's first institution of higher education that formally included neurobiology in the curriculum of an educational department, having done so as early as 1922. The responsibility of teaching neurobiology to educators was assigned to Professor Christofredo Jakob (1866-1956). In the present article, we highlight Jakob's emphasis on interdisciplinarity and, in particular, on the neuroscientific foundations of education, including special education.

Network for Early Onset Cystic Kidney Diseases—A Comprehensive Multidisciplinary Approach to Hereditary Cystic Kidney Diseases in Childhood

PubMed Central

König, Jens Christian; Titieni, Andrea; Konrad, Martin; Bergmann, C.

2018-01-01

Hereditary cystic kidney diseases comprise a complex group of genetic disorders representing one of the most common causes of end-stage renal failure in childhood. The main representatives are autosomal recessive polycystic kidney disease, nephronophthisis, Bardet–Biedl syndrome, and hepatocyte nuclear factor-1beta nephropathy. Within the last years, genetic efforts have brought tremendous progress for the molecular understanding of hereditary cystic kidney diseases identifying more than 70 genes. Yet, genetic heterogeneity, phenotypic variability, a lack of reliable genotype–phenotype correlations and the absence of disease-specific biomarkers remain major challenges for physicians treating children with cystic kidney diseases. To tackle these challenges comprehensive scientific approaches are urgently needed that match the ongoing “revolution” in genetics and molecular biology with an improved efficacy of clinical data collection. Network for early onset cystic kidney diseases (NEOCYST) is a multidisciplinary, multicenter collaborative combining a detailed collection of clinical data with translational scientific approaches addressing the genetic, molecular, and functional background of hereditary cystic kidney diseases. Consisting of seven work packages, including an international registry as well as a biobank, NEOCYST is not only dedicated to current scientific questions, but also provides a platform for longitudinal clinical surveillance and provides precious sources for high-quality research projects and future clinical trials. Funded by the German Federal Government, the NEOCYST collaborative started in February 2016. Here, we would like to introduce the rationale, design, and objectives of the network followed by a short overview on the current state of progress. PMID:29497606

Pulvinar sign in a case of anti-HU paraneoplastic encephalitis

PubMed Central

Gagnon, Maude-Marie; Savard, Martin; Émond, François

2016-01-01

This article reports the case of a 68-year-old patient with anti-HU antibodies paraneoplastic encephalitis. The clinical manifestations were atypical and the paraclinical work-up, notably the magnetic resonance imaging (MRI) showing bilateral posterior thalamic hyperintensities (pulvinar sign), misleadingly pointed towards a variant Creutzfeld–Jakob disease. After presenting the case, the differential diagnosis of the pulvinar sign is discussed along with other important diagnostic considerations. PMID:27558994

Impact of Genetics on the Diagnosis and Treatment of Renal Cancer

PubMed Central

Singer, Eric A.; Bratslavsky, Gennady; Middelton, Lindsay; Srinivasan, Ramaprasad; Linehan, W. Marston

2011-01-01

Kidney cancer is a heterogeneous disease comprised of a number of histologic subtypes, each associated with unique genetic mutations, clinical features, and sensitivity to treatment. By examining families affected with the hereditary kidney cancer syndromes von Hippel-Lindau, hereditary papillary renal cell carcinoma, hereditary leiomyomatosis and renal cell carcinoma, and Birt-Hogg-Dube', researchers have been able to identify the genes responsible for these syndromes. This work has revealed that kidney cancer is fundamentally a metabolic disorder, and as such, novel targeted therapies specific to their molecular biology have been developed and employed in both the hereditary and sporadic forms of renal cell carcinoma. PMID:21128028

DNA testing in neurologic diseases.

PubMed

O'Brien, D P; Leeb, T

2014-01-01

DNA testing is available for a growing number of hereditary diseases in neurology and other specialties. In addition to guiding breeding decisions, DNA tests are important tools in the diagnosis of diseases, particularly in conditions for which clinical signs are relatively nonspecific. DNA testing also can provide valuable insight into the risk of hereditary disease when decisions about treating comorbidities are being made. Advances in technology and bioinformatics will make broad screening for potential disease-causing mutations available soon. As DNA tests come into more common use, it is critical that clinicians understand the proper application and interpretation of these test results. Copyright © 2014 by the American College of Veterinary Internal Medicine.

"Does Broca's Area Exist?:" Christofredo Jakob's 1906 Response to Pierre Marie's Holistic Stance

ERIC Educational Resources Information Center

Tsapkini, Kyrana; Vivas, Ana B.; Triarhou, Lazaros C.

2008-01-01

In 1906, Pierre Marie triggered a heated controversy and an exchange of articles with Jules Dejerine over the localization of language functions in the human brain. The debate spread internationally. One of the timeliest responses, that appeared in print 1 month after Marie's paper, came from Christofredo Jakob, a Bavarian-born neuropathologist…

Open-heart surgery using a centrifugal pump: a case of hereditary spherocytosis.

PubMed

Matsuzaki, Yuichi; Tomioka, Hideyuki; Saso, Masaki; Azuma, Takashi; Saito, Satoshi; Aomi, Shigeyuki; Yamazaki, Kenji

2016-08-26

Hereditary spherocytosis is a genetic, frequently familial hemolytic blood disease characterized by varying degrees of hemolytic anemia, splenomegaly, and jaundice. There are few reports on adult open-heart surgery for patients with hereditary spherocytosis. We report a rare case of an adult open-heart surgery associated with hereditary spherocytosis. A 63-year-old man was admitted for congestive heart failure due to bicuspid aortic valve, aortic valve regurgitation, and sinus of subaortic aneurysm. The family history, the microscopic findings of the blood smear, and the characteristic osmotic fragility confirmed the diagnosis of hereditary spherocytosis. Furthermore, splenectomy had not been undertaken preoperatively. The patient underwent a successful operation by means of a centrifugal pump. Haptoglobin was used during the cardiopulmonary bypass, and a biological valve was selected to prevent hemolysis. No significant hemolysis occurred intraoperatively or postoperatively. There are no previous reports of patients with hereditary spherocytosis, and bicuspid aortic valve. We have successfully performed an adult open-heart surgery using a centrifugal pump in an adult patient suffering from hereditary spherocytosis and bicuspid aortic valve.

Mechanistic basis of an epistatic interaction reducing age at onset in hereditary spastic paraplegia.

PubMed

Newton, Timothy; Allison, Rachel; Edgar, James R; Lumb, Jennifer H; Rodger, Catherine E; Manna, Paul T; Rizo, Tania; Kohl, Zacharias; Nygren, Anders O H; Arning, Larissa; Schüle, Rebecca; Depienne, Christel; Goldberg, Lisa; Frahm, Christiane; Stevanin, Giovanni; Durr, Alexandra; Schöls, Ludger; Winner, Beate; Beetz, Christian; Reid, Evan

2018-05-01

Many genetic neurological disorders exhibit variable expression within affected families, often exemplified by variations in disease age at onset. Epistatic effects (i.e. effects of modifier genes on the disease gene) may underlie this variation, but the mechanistic basis for such epistatic interactions is rarely understood. Here we report a novel epistatic interaction between SPAST and the contiguous gene DPY30, which modifies age at onset in hereditary spastic paraplegia, a genetic axonopathy. We found that patients with hereditary spastic paraplegia caused by genomic deletions of SPAST that extended into DPY30 had a significantly younger age at onset. We show that, like spastin, the protein encoded by SPAST, the DPY30 protein controls endosomal tubule fission, traffic of mannose 6-phosphate receptors from endosomes to the Golgi, and lysosomal ultrastructural morphology. We propose that additive effects on this pathway explain the reduced age at onset of hereditary spastic paraplegia in patients who are haploinsufficient for both genes.

The Identification of Alpha-Synuclein as the First Parkinson Disease Gene

PubMed Central

Nussbaum, Robert L.

2017-01-01

In this Commentary, I describe the events that led from an NINDS-sponsored Workshop on Parkinson Disease Research in 1995, where I was asked to speak about the genetics of Parkinson disease, to the identification a mere two years later of a mutation in alpha-synuclein as the cause of autosomal dominant Parkinson disease in the Contursi kindred. I review the steps we took to first map and then find the mutation in the alpha-synuclein locus and describe the obstacles and the role of serendipity in facilitating the work. Although alpha-synuclein mutations are a rare cause of hereditary PD, the importance of this finding goes far beyond the rare families with hereditary disease because it pinpointed alpha-synuclein as a key contributor to the far more common sporadic form of Parkinson disease. This work confirms William Harvey’s observation from 350 years ago that studying rarer forms of a disease is an excellent way to understand the more common forms of that disease. The identification of synuclein’s role in hereditary Parkinson disease has opened new avenues of research into the pathogenesis and potential treatments of the common form of Parkinson disease that affects many millions of Americans and tens of millions of human beings worldwide. PMID:28282812

The Identification of Alpha-Synuclein as the First Parkinson Disease Gene.

PubMed

Nussbaum, Robert L

2017-01-01

In this Commentary, I describe the events that led from an NINDS-sponsored Workshop on Parkinson Disease Research in 1995, where I was asked to speak about the genetics of Parkinson disease, to the identification a mere two years later of a mutation in alpha-synuclein as the cause of autosomal dominant Parkinson disease in the Contursi kindred. I review the steps we took to first map and then find the mutation in the alpha-synuclein locus and describe the obstacles and the role of serendipity in facilitating the work. Although alpha-synuclein mutations are a rare cause of hereditary PD, the importance of this finding goes far beyond the rare families with hereditary disease because it pinpointed alpha-synuclein as a key contributor to the far more common sporadic form of Parkinson disease. This work confirms William Harvey's observation from 350 years ago that studying rarer forms of a disease is an excellent way to understand the more common forms of that disease. The identification of synuclein's role in hereditary Parkinson disease has opened new avenues of research into the pathogenesis and potential treatments of the common form of Parkinson disease that affects many millions of Americans and tens of millions of human beings worldwide.

[Progress in research on pathogenic genes and gene therapy for inherited retinal diseases].

PubMed

Zhu, Ling; Cao, Cong; Sun, Jiji; Gao, Tao; Liang, Xiaoyang; Nie, Zhipeng; Ji, Yanchun; Jiang, Pingping; Guan, Minxin

2017-02-10

Inherited retinal diseases (IRDs), including retinitis pigmentosa, Usher syndrome, Cone-Rod degenerations, inherited macular dystrophy, Leber's congenital amaurosis, Leber's hereditary optic neuropathy are the most common and severe types of hereditary ocular diseases. So far more than 200 pathogenic genes have been identified. With the growing knowledge of the genetics and mechanisms of IRDs, a number of gene therapeutic strategies have been developed in the laboratory or even entered clinical trials. Here the progress of IRD research on the pathogenic genes and therapeutic strategies, particularly gene therapy, are reviewed.

A network medicine approach to quantify distance between hereditary disease modules on the interactome

NASA Astrophysics Data System (ADS)

Caniza, Horacio; Romero, Alfonso E.; Paccanaro, Alberto

2015-12-01

We introduce a MeSH-based method that accurately quantifies similarity between heritable diseases at molecular level. This method effectively brings together the existing information about diseases that is scattered across the vast corpus of biomedical literature. We prove that sets of MeSH terms provide a highly descriptive representation of heritable disease and that the structure of MeSH provides a natural way of combining individual MeSH vocabularies. We show that our measure can be used effectively in the prediction of candidate disease genes. We developed a web application to query more than 28.5 million relationships between 7,574 hereditary diseases (96% of OMIM) based on our similarity measure.

Brazilian Guidelines for Hereditary Angioedema Management - 2017 Update Part 1: Definition, Classification and Diagnosis.

PubMed

Giavina-Bianchi, Pedro; Arruda, Luisa Karla; Aun, Marcelo V; Campos, Regis A; Chong-Neto, Herberto J; Constantino-Silva, Rosemeire N; Fernandes, Fátima R; Ferraro, Maria F; Ferriani, Mariana P L; França, Alfeu T; Fusaro, Gustavo; Garcia, Juliana F B; Komninakis, Shirley; Maia, Luana S M; Mansour, Eli; Moreno, Adriana S; Motta, Antonio A; Pesquero, João B; Portilho, Nathalia; Rosário, Nelson A; Serpa, Faradiba S; Solé, Dirceu; Takejima, Priscila; Toledo, Eliana; Valle, Solange O.R; Veronez, Camila L; Grumach, Anete S

2018-01-01

Hereditary angioedema is an autosomal dominant disease characterized by recurrent angioedema attacks with the involvement of multiple organs. The disease is unknown to many health professionals and is therefore underdiagnosed. Patients who are not adequately diagnosed and treated have an estimated mortality rate ranging from 25% to 40% due to asphyxiation by laryngeal angioedema. Intestinal angioedema is another important and incapacitating presentation that may be the main or only manifestation during an attack. In this article, a group of experts from the "Associação Brasileira de Alergia e Imunologia (ASBAI)" and the "Grupo de Estudos Brasileiro em Angioedema Hereditário (GEBRAEH)" has updated the Brazilian guidelines for the diagnosis and treatment of hereditary angioedema.

Hereditary hemorrhagic telangiectasia patient presenting with brain abscess due to silent pulmonary arteriovenous malformation.

PubMed

Themistocleous, Marios; Giakoumettis, Dimitrios; Mitsios, Andreas; Anagnostopoulos, Christos; Kalyvas, Aristoteles; Koutsarnakis, Christos

2016-01-01

Hereditary hemorrhagic telangiectasia is a rare autosomal dominant inherited disease that is usually complicated by visceral vascular malformations. Patients harboring such malformations are at increased risk of brain abscess formation, which despite advances in diagnostic and surgical methods remains a life threatening medical emergency with high mortality and morbidity rates. In the present report we describe a case of cerebral abscess due to silent pulmonary arteriovenous malformation (AVM) in a young patient previously undiagnosed for hereditary hemorrhagic telangiectasia syndrome (HHT).

Previously undiagnosed hereditary spherocytosis in a patient with jaundice and pyelonephritis: a case report.

PubMed

Tateno, Yuki; Suzuki, Ryoji; Kitamura, Yukihiro

2016-12-01

Hereditary spherocytosis is autosomal dominant inherited extravascular hemolytic disorder and is the commonest cause of inherited hemolysis in northern Europe and the United States. The classical clinical features of hereditary spherocytosis are anemia, jaundice, and splenomegaly. However, all of these classical features are not always revealed in the case of mild hemolysis or when hemolysis is well compensated. Patients with hereditary spherocytosis may remain undiagnosed for years if their hemolysis is mild. A 42-year-old Asian woman presented to our clinic with a sudden onset of high fever with shaking chills and jaundice, suggesting septicemia; however, following detailed investigation, the patient was diagnosed with pyelonephritis and accelerated hemolysis of hereditary spherocytosis due to infection. It is important to note that transient anemia or jaundice can sometimes be the only initial presenting symptoms in cases of undiagnosed latent hereditary spherocytosis. This case also highlights the fact that physicians should consider concomitant hemolytic disease in patients in whom jaundice and infections that rarely cause jaundice coexist.

Development of a disease-specific quality of life questionnaire for adult patients with hereditary angioedema due to C1 inhibitor deficiency (HAE-QoL): Spanish multi-centre research project.

PubMed

Prior, Nieves; Remor, Eduardo; Gómez-Traseira, Carmen; López-Serrano, Concepción; Cabañas, Rosario; Contreras, Javier; Campos, Ángel; Cardona, Victoria; Cimbollek, Stefan; González-Quevedo, Teresa; Guilarte, Mar; de Rojas, Dolores Hernández Fernández; Marcos, Carmen; Rubio, María; Tejedor-Alonso, Miguel Ángel; Caballero, Teresa

2012-07-20

There is a need for a disease-specific instrument for assessing health-related quality of life in adults with hereditary angioedema due to C1 inhibitor deficiency, a rare, disabling and life-threatening disease. In this paper we report the protocol for the development and validation of a specific questionnaire, with details on the results of the process of item generation, domain selection, and the expert and patient rating phase. Semi-structured interviews were completed by 45 patients with hereditary angioedema and 8 experts from 8 regions in Spain. A qualitative content analysis of the responses was carried out. Issues raised by respondents were grouped into categories. Content analysis identified 240 different responses, which were grouped into 10 conceptual domains. Sixty- four items were generated. A total of 8 experts and 16 patients assessed the items for clarity, relevance to the disease, and correct dimension assignment. The preliminary version of the specific health-related quality of life questionnaire for hereditary angioedema (HAE-QoL v 1.1) contained 44 items grouped into 9 domains. To the best of our knowledge, this is the first multi-centre research project that aims to develop a specific health-related quality of life questionnaire for adult patients with hereditary angioedema due to C1 inhibitor deficiency. A preliminary version of the specific HAE-QoL questionnaire was obtained. The qualitative analysis of interviews together with the expert and patient rating phase helped to ensure content validity. A pilot study will be performed to assess the psychometric properties of the questionnaire and to decide on the final version.

Hereditary Parkinson s Disease Natural History Protocol

ClinicalTrials.gov

2018-03-27

Parkinson Disease 6, Early-Onset; Parkinson Disease (Autosomal Recessive, Early Onset) 7, Human; Parkinson Disease Autosomal Recessive, Early Onset; Parkinson Disease, Autosomal Recessive Early-Onset, Digenic, Pink1/Dj1

Mutation analysis of genes within the dynactin complex in a cohort of hereditary peripheral neuropathies.

PubMed

Tey, S; Ahmad-Annuar, A; Drew, A P; Shahrizaila, N; Nicholson, G A; Kennerson, M L

2016-08-01

The cytoplasmic dynein-dynactin genes are attractive candidates for neurodegenerative disorders given their functional role in retrograde transport along neurons. The cytoplasmic dynein heavy chain (DYNC1H1) gene has been implicated in various neurodegenerative disorders, and dynactin 1 (DCTN1) genes have been implicated in a wide spectrum of disorders including motor neuron disease, Parkinson's disease, spinobulbar muscular atrophy and hereditary spastic paraplegia. However, the involvement of other dynactin genes with inherited peripheral neuropathies (IPN) namely, hereditary sensory neuropathy, hereditary motor neuropathy and Charcot-Marie-Tooth disease is under reported. We screened eight genes; DCTN1-6 and ACTR1A and ACTR1B in 136 IPN patients using whole-exome sequencing and high-resolution melt (HRM) analysis. Eight non-synonymous variants (including one novel variant) and three synonymous variants were identified. Four variants have been reported previously in other studies, however segregation analysis within family members excluded them from causing IPN in these families. No variants of disease significance were identified in this study suggesting the dynactin genes are unlikely to be a common cause of IPNs. However, with the ease of querying gene variants from exome data, these genes remain worthwhile candidates to assess unsolved IPN families for variants that may affect the function of the proteins. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Genes for Hereditary Sensory and Autonomic Neuropathies: A Genotype-Phenotype Correlation

ERIC Educational Resources Information Center

Rotthier, Annelies; Baets, Jonathan; De Vriendt, Els; Jacobs, An; Auer-Grumbach, Michaela; Levy, Nicolas; Bonello-Palot, Nathalie; Kilic, Sara Sebnem; Weis, Joachim; Nascimento, Andres; Swinkels, Marielle; Kruyt, Moyo C.; Jordanova, Albena; De Jonghe, Peter; Timmerman, Vincent

2009-01-01

Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders characterized by axonal atrophy and degeneration, exclusively or predominantly affecting the sensory and autonomic neurons. So far, disease-associated mutations have been identified in seven genes: two genes for autosomal dominant ("SPTLC1"…

Genetics Home Reference: distal hereditary motor neuropathy, type V

MedlinePlus

... PubMed Irobi J, De Jonghe P, Timmerman V. Molecular genetics of distal hereditary motor neuropathies. Hum Mol Genet. 2004 Oct 1;13 Spec No 2:R195-202. Review. Citation on PubMed Ito D, Suzuki N. Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases. ...

Analysis of Genetic Mutations in a Cohort of Hereditary Optic Neuropathy in Shanghai, China.

PubMed

Gan, Dekang; Li, Mengwei; Wu, Jihong; Sun, Xinghuai; Tian, Guohong

2017-01-01

To evaluate the clinical classification and characteristics of hereditary optic neuropathy patients in a single center in China. Retrospective case study. Patients diagnosed with hereditary optic neuropathy between January 2014 and December 2015 in the neuro-ophthalmology division in Shanghai Eye and ENT Hospital of Fudan University were recruited. Clinical features as well as visual field, brain/orbital MRI, and spectrum domain optical coherence tomography (SD-OCT) were analyzed. Eighty-two patients diagnosed by gene test were evaluated, including 66 males and 16 females. The mean age of the patients was 19.4 years (range, 5-46 years). A total of 158 eyes were analyzed, including 6 unilateral, 61 bilateral, and 15 sequential. The median duration of the disease was 0.5 year (range, 0.1-20 years). Genetic test identified 68 patients with Leber hereditary optic neuropathy, 9 with dominant optic neuropathy, and 2 with a Wolfram gene mutation. There was also one case of hereditary spastic paraplegia, spinocerebellar ataxia, and polymicrogyria with optic nerve atrophy, respectively. Leber hereditary optic neuropathy is the most common detected type of hereditary optic neuropathy in Shanghai, China. The detection of other autosomal mutations in hereditary optic neuropathy is limited by the currently available technique.

A comprehensive custom panel design for routine hereditary cancer testing: preserving control, improving diagnostics and revealing a complex variation landscape.

PubMed

Castellanos, Elisabeth; Gel, Bernat; Rosas, Inma; Tornero, Eva; Santín, Sheila; Pluvinet, Raquel; Velasco, Juan; Sumoy, Lauro; Del Valle, Jesús; Perucho, Manuel; Blanco, Ignacio; Navarro, Matilde; Brunet, Joan; Pineda, Marta; Feliubadaló, Lidia; Capellá, Gabi; Lázaro, Conxi; Serra, Eduard

2017-01-04

We wanted to implement an NGS strategy to globally analyze hereditary cancer with diagnostic quality while retaining the same degree of understanding and control we had in pre-NGS strategies. To do this, we developed the I2HCP panel, a custom bait library covering 122 hereditary cancer genes. We improved bait design, tested different NGS platforms and created a clinically driven custom data analysis pipeline. The I2HCP panel was developed using a training set of hereditary colorectal cancer, hereditary breast and ovarian cancer and neurofibromatosis patients and reached an accuracy, analytical sensitivity and specificity greater than 99%, which was maintained in a validation set. I2HCP changed our diagnostic approach, involving clinicians and a genetic diagnostics team from panel design to reporting. The new strategy improved diagnostic sensitivity, solved uncertain clinical diagnoses and identified mutations in new genes. We assessed the genetic variation in the complete set of hereditary cancer genes, revealing a complex variation landscape that coexists with the disease-causing mutation. We developed, validated and implemented a custom NGS-based strategy for hereditary cancer diagnostics that improved our previous workflows. Additionally, the existence of a rich genetic variation in hereditary cancer genes favors the use of this panel to investigate their role in cancer risk.

[Asymptomatic classical hereditary xanthinuria type 1].

PubMed

Yakubov, Renata; Nir, Vered; Kassem, Eiass; Klein-Kremer, Adi

2012-06-01

We report on a girl who was diagnosed with classical hereditary xanthinuria due to an incidental finding of extremely low Levels of uric acid in the blood. The girl is compLetely asymptomatic. Hereditary xanthinuria is a rare autosomal recessive disease that usually causes early urolithiasis but may cause rheumatoid arthritis-like disease and even be associated with defects in the formation of bone, hair and teeth. In Israel it has mostly been described in patients of Bedouin origin. Throughout the world, only about 150 cases have been described; about two thirds of these patients were asymptomatic. Since the clinical presentation and age of symptom appearance are diverse, the case raises questions as to the required follow-up of these patients and as to whether a low oxalate diet should be initiated.

[A medico-genetic description of inhabitants of two regions of the Kransnodar Krai].

PubMed

Mamedova, R A; Kadoshnikova, M Iu; Galkina, V A; Klebnikova, O B; Mikhaĭlova, L K; Rudenskaia, G E; Ginter, E K

1999-01-01

The spectrum and prevalence rate of hereditary pathology in Kanevskii and Bryukhovetskii raions (districts) of Krasnodar krai (territory) were analyzed. The total size of the studied population was 145,937. The prevalence rate of monogenic hereditary pathology was estimated. This value was 1.08 +/- 0.08, 0.72 +/- 0.07, and 0.20 +/- 0.06 per 1000 people for autosomal dominant (AD), autosomal recessive (AR), and X-linked (XL) recessive diseases, respectively. Forty-two AD (158 affected persons in 82 families), 32 AR (105 affected persons in 82 families), and 6 XL disease entities (13 affected persons in 8 families) were found. A slight genetic subdivision was found in the populations of Kanevskii and Bryukhovetskii raions. However, it was not found to affect the prevalence of hereditary pathology.

Familial Renal Cancer: Molecular Genetics and Surgical Management

PubMed Central

Barrisford, Glen W.; Singer, Eric A.; Rosner, Inger L.; Linehan, W. Marston; Bratslavsky, Gennady

2011-01-01

Familial renal cancer (FRC) is a heterogeneous disorder comprised of a variety of subtypes. Each subtype is known to have unique histologic features, genetic alterations, and response to therapy. Through the study of families affected by hereditary forms of kidney cancer, insights into the genetic basis of this disease have been identified. This has resulted in the elucidation of a number of kidney cancer gene pathways. Study of these pathways has led to the development of novel targeted molecular treatments for patients affected by systemic disease. As a result, the treatments for families affected by von Hippel-Lindau (VHL), hereditary papillary renal carcinoma (HPRC), hereditary leiomyomatosis renal cell carcinoma (HLRCC), and Birt-Hogg-Dubé (BHD) are rapidly changing. We review the genetics and contemporary surgical management of familial forms of kidney cancer. PMID:22312516

Hereditary cerebral hemorrhage with amyloidosis in patients of Dutch origin is related to Alzheimer disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

van Duinen, S.G.; Castano, E.M.; Prelli, F.

1987-08-01

Hereditary cerebral hemorrhage with amyloidosis in Dutch patients is an autosomal dominant form of vascular amyloidosis restricted to the leptomeninges and cerebral cortex. Clinically the disease is characterized by cerebral hemorrhages leading to an early death. Immunohistochemical studies of five patients revealed that the vascular amyloid deposits reacted intensely with an antiserum raised against a synthetic peptide homologous to the Alzheimer disease-related ..beta..-protein. Silver stain-positive, senile plaque-like structures were also labeled by the antiserum, yet these lesions lacked the dense amyloid cores present in typical plaques of Alzheimer disease. No neurofibrillary tangles were present. Amyloid fibrils were purified from themore » leptomeningeal vessels of one patient who clinically had no signs of dementia. The protein had a molecular weight of approx. 4000 and its partial amino acid sequence to position 21 showed homology to the ..beta..-protein of Alzheimer disease and Down syndrome. These results suggest that hereditary cerebral hemorrhage with amyloidosis of Dutch origin is pathogenetically related to Alzheimer disease and support the concept that the initial amyloid deposition in this disorder occurs in the vessel walls before damaging the brain parenchyma. Thus, deposition of ..beta..-protein in brain tissue seems to be related to a spectrum of diseases involving vascular syndromes, progressive dementia, or both.« less

Natural History Study of Children With Metachromatic Leukodystrophy

ClinicalTrials.gov

2016-04-19

Lipid Metabolism Disorders; Metachromatic Leukodystrophy (MLD); Nervous System Diseases; Brain Diseases; Central Nervous System Diseases; Demyelinating Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Sphingolipidoses; Hereditary Central Nervous System Demyelinating Diseases; Metabolic Inborn Brain Diseases; Lysosomal Storage Diseases; Metabolic Diseases; Sulfatidosis

Hereditary angioneurotic edema treated by partial uvulectomy.

PubMed

Waeckerle, J F; Smith, H A; McNabney, W K

1976-06-01

Hereditary angioneurotic edema (HANE) is a rare familial disease of C1 esterase inhibitor deficiency that produces recurring attacks of acute, circumscribed, noninflammatory edema. The technique of partial uvulectomy to treat HANE can reduce the mortality from this condition due to asphyxiation. Three cases in which partial uvulectomy was the successful mode of treatment are described.

Longitudinal Cerebral Blood Flow Changes during Speech in Hereditary Ataxia

ERIC Educational Resources Information Center

Sidtis, John J.; Strother, Stephen C.; Naoum, Ansam; Rottenberg, David A.; Gomez, Christopher

2010-01-01

The hereditary ataxias constitute a group of degenerative diseases that progress over years or decades. With principal pathology involving the cerebellum, dysarthria is an early feature of many of the ataxias. Positron emission tomography was used to study regional cerebral blood flow changes during speech production over a 21 month period in a…

Genetic disorder in carbohydrates metabolism: hereditary fructose intolerance associated with celiac disease.

PubMed

Păcurar, Daniela; Leşanu, Gabriela; Dijmărescu, Irina; Ţincu, Iulia Florentina; Gherghiceanu, Mihaela; Orăşeanu, Dumitru

2017-01-01

Celiac disease (CD) has been associated with several genetic and immune disorders, but association between CD and hereditary fructose intolerance (HFI) is extremely rare. HFI is an autosomal recessive disease caused by catalytic deficiency of aldolase B (fructose-1,6-bisphosphate aldolase). We report the case of a 5-year-old boy suffering from CD, admitted with an initial diagnosis of Reye's-like syndrome. He presented with episodic unconsciousness, seizures, hypoglycemia, hepatomegaly and abnormal liver function. The patient has been on an exclusion diet for three years, but he still had symptoms: stunting, hepatomegaly, high transaminases, but tissue transglutaminase antibodies were negative. Liver biopsy showed hepatic steatosis and mitochondrial damage. The dietary history showed an aversion to fruits, vegetables and sweet-tasting foods. The fructose tolerance test was positive, revealing the diagnostic of hereditary fructose intolerance. Appropriate dietary management and precautions were recommended. The patient has been symptom-free and exhibited normal growth and development until 10 years of age.

Prion Protein Devoid of the Octapeptide Repeat Region Delays Bovine Spongiform Encephalopathy Pathogenesis in Mice.

PubMed

Hara, Hideyuki; Miyata, Hironori; Das, Nandita Rani; Chida, Junji; Yoshimochi, Tatenobu; Uchiyama, Keiji; Watanabe, Hitomi; Kondoh, Gen; Yokoyama, Takashi; Sakaguchi, Suehiro

2018-01-01

Conformational conversion of the cellular isoform of prion protein, PrP C , into the abnormally folded, amyloidogenic isoform, PrP Sc , is a key pathogenic event in prion diseases, including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy (BSE) in animals. We previously reported that the octapeptide repeat (OR) region could be dispensable for converting PrP C into PrP Sc after infection with RML prions. We demonstrated that mice transgenically expressing mouse PrP with deletion of the OR region on the PrP knockout background, designated Tg(PrPΔOR)/ Prnp 0 / 0 mice, did not show reduced susceptibility to RML scrapie prions, with abundant accumulation of PrP Sc ΔOR in their brains. We show here that Tg(PrPΔOR)/ Prnp 0 / 0 mice were highly resistant to BSE prions, developing the disease with markedly elongated incubation times after infection with BSE prions. The conversion of PrPΔOR into PrP Sc ΔOR was markedly delayed in their brains. These results suggest that the OR region may have a crucial role in the conversion of PrP C into PrP Sc after infection with BSE prions. However, Tg(PrPΔOR)/ Prnp 0 / 0 mice remained susceptible to RML and 22L scrapie prions, developing the disease without elongated incubation times after infection with RML and 22L prions. PrP Sc ΔOR accumulated only slightly less in the brains of RML- or 22L-infected Tg(PrPΔOR)/ Prnp 0 / 0 mice than PrP Sc in control wild-type mice. Taken together, these results indicate that the OR region of PrP C could play a differential role in the pathogenesis of BSE prions and RML or 22L scrapie prions. IMPORTANCE Structure-function relationship studies of PrP C conformational conversion into PrP Sc are worthwhile to understand the mechanism of the conversion of PrP C into PrP Sc We show here that, by inoculating Tg(PrPΔOR)/ Prnp 0 / 0 mice with the three different strains of RML, 22L, and BSE prions, the OR region could play a differential role in the conversion of PrP C into PrP Sc after infection with RML or 22L scrapie prions and BSE prions. PrPΔOR was efficiently converted into PrP Sc ΔOR after infection with RML and 22L prions. However, the conversion of PrPΔOR into PrP Sc ΔOR was markedly delayed after infection with BSE prions. Further investigation into the role of the OR region in the conversion of PrP C into PrP Sc after infection with BSE prions might be helpful for understanding the pathogenesis of BSE prions. Copyright © 2017 American Society for Microbiology.

[Sketches of Swiss psychiatry in the generation after Eugen Bleuler and Sigmund Freud. With personal recollections].

PubMed

Weber, Kaspar

2009-01-01

Focussing on the leading staff of the psychiatric universitiy clinic of Waldau/Bern, the author sketches the reception of psychoanalysis in Switzerland around 1940. It ranged from outright rejection (Ernst Grünthal) via various forms of skepticism based on superficial (Jakob Klaesi) or thorough familiarity with Freud's writings (Jakob Wyrsch, Arnold Weber) to the discipleship of an analysand of Freud (Ernst Blum).

Color matches in diseased eyes with good acuity: detection of deficits in cone optical density and in chromatic discrimination

NASA Astrophysics Data System (ADS)

Swanson, William H.; Fish, Gary E.

1995-10-01

Reduced foveal cone optical density in diseased eyes with normal acuity can affect color matches. Using field diameters of 1 deg, 2 deg, 4 deg, and 8 deg, we measured mean color-match midpoints and match widths in patients who had good acuity and who hereditary macular degeneration ( n=12 ), retinitis pigmentosa ( n=19 ), and glaucoma ( n=18 ). Results were compared with those for normal observers of comparable ages. Mean color-match midpoints were abnormal only for the population with hereditary macular degeneration, indicating a reduction in cone optical density in the central 4 deg. Mean color-match widths were enlarged for both hereditary macular degeneration and retinitis pigmentosa, a result consistent with a reduction in the number of foveal cones. chromatic discrimination, macular degeneration, retinitis pigmentosa, glaucoma.

Diagnostic power of laboratory tests for hereditary spherocytosis: a comparison study in 150 patients grouped according to molecular and clinical characteristics

PubMed Central

Bianchi, Paola; Fermo, Elisa; Vercellati, Cristina; Marcello, Anna P.; Porretti, Laura; Cortelezzi, Agostino; Barcellini, Wilma; Zanella, Alberto

2012-01-01

Background The laboratory diagnosis of hereditary spherocytosis commonly relies on NaCl-based or glycerol-based red cell osmotic fragility tests; more recently, an assay directly targeting the hereditary spherocytosis molecular defect (eosin-5′-maleimide-binding test) has been proposed. None of the available tests identifies all cases of hereditary spherocytosis. Design and Methods We compared the performances of the eosin-5′-maleimide-binding test, NaCl-osmotic fragility studies on fresh and incubated blood, the glycerol lysis test, the acidified glycerol lysis test, and the Pink test on a series of 150 patients with hereditary spherocytosis grouped according to clinical phenotype and the defective protein, with the final aim of finding the combination of tests associated with the highest diagnostic power, even in the mildest cases of hereditary spherocytosis. Results The eosin-5′-maleimide-binding test had a sensitivity of 93% and a specificity of 98% for detecting hereditary spherocytosis: the sensitivity was independent of the type and amount of molecular defect and of the clinical phenotype. The acidified glycerol lysis test and Pink test showed comparable sensitivity (95% and 91%). The sensitivity of NaCl osmotic fragility tests, commonly considered the gold standard for the diagnosis of hereditary spherocytosis, was 68% on fresh blood and 81% on incubated blood, and further decreased in compensated cases (53% and 64%, respectively). The combination of the eosin-5′-maleimide-binding test and acidified glycerol lysis test enabled all patients with hereditary spherocytosis to be identified. The eosin-5′-maleimide-binding test showed the greatest disease specificity. Conclusions Each type of test fails to diagnose some cases of hereditary spherocytosis. The association of an eosin-5′-maleimide-binding test and an acidified glycerol lysis test enabled identification of all patients with hereditary spherocytosis in this series and, therefore, represents a currently effective diagnostic strategy for hereditary spherocytosis including mild/compensated cases. PMID:22058213

Blood Disorders

MedlinePlus

... become hard, sticky, and shaped like a C. Thalassemia Red blood cell disorder. Von Willebrand Disease Blood ... Hemophilia Hereditary Hemorrhagic Telangiectasia (HHT) Sickle Cell Disease Thalassemia Vitamin K Deficiency Bleeding Von Willebrand Disease Women’s ...

Semicentennial tribute to the ingenious neurobiologist Christfried Jakob (1866-1956). 1. Works from Germany and the first Argentina period, 1891-1913.

PubMed

Triarhou, Lazaros C; del Cerro, Manuel

2006-01-01

This study, and the companion paper that follows, pays homage to the life and work of Christfried (also Christian or Christofredo) Jakob, a German-born neuropathologist who adopted Argentina as his country of vocation. Rated by von Economo and Koskinas among the three most important pre-1925 cortical neuro-anatomists, alongside Ramón y Cajal, Jakob is little known in the English literature. He has left an impressive record of publications, 30 richly illustrated monographs and 200 articles that span over a vast array of neurological themes, including cortical development and evolution, and the visceral brain. The present paper reviews works from his German years and the first visit to Argentina in 1899-1910. The companion paper covers his works (all in Spanish) during his 'second Argentina period', after 1913. Copyright (c) 2006 S. Karger AG, Basel.

An Analysis of the Symptomatic Domains Most Relevant to Charcot Marie Tooth Neuropathy (CMT) Patients

ClinicalTrials.gov

2017-06-09

Charcot Marie Tooth Disease (CMT); Hereditary Sensory and Motor Neuropathy; Nerve Compression Syndromes; Tooth Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Heredodegenerative Disorders, Nervous System

MANAGEMENT OF ENDOCRINE DISEASE: Outcome of adrenal sparing surgery in heritable pheochromocytoma.

PubMed

Castinetti, F; Taieb, D; Henry, J F; Walz, M; Guerin, C; Brue, T; Conte-Devolx, B; Neumann, H P H; Sebag, F

2016-01-01

The management of hereditary pheochromocytoma has drastically evolved in the last 20 years. Bilateral pheochromocytoma does not increase mortality in MEN2 or von Hippel-Lindau (VHL) mutation carriers who are followed regularly, but these mutations induce major morbidities if total bilateral adrenalectomy is performed. Cortical sparing adrenal surgery may be proposed to avoid definitive adrenal insufficiency. The surgical goal is to leave sufficient cortical tissue to avoid glucocorticoid replacement therapy. This approach was achieved by the progressive experience of minimally invasive surgery via the transperitoneal or retroperitoneal route. Cortical sparing adrenal surgery exhibits <5% significant recurrence after 10 years of follow-up and normal glucocorticoid function in more than 50% of the cases. Therefore, cortical sparing adrenal surgery should be systematically considered in the management of all patients with MEN2 or VHL hereditary pheochromocytoma. Hereditary pheochromocytoma is a rare disease, and a randomized trial comparing cortical sparing vs classical adrenalectomy is probably not possible. This lack of data most likely explains why cortical sparing surgery has not been adopted in most expert centers that perform at least 20 procedures per year for the treatment of this disease. This review examined recent data to provide insight into the technique, its indications, and the results and subsequent follow-up in the management of patients with hereditary pheochromocytoma with a special emphasis on MEN2. © 2016 European Society of Endocrinology.

Oral manifestations, dental management, and a rare homozygous mutation of the PRDM12 gene in a boy with hereditary sensory and autonomic neuropathy type VIII: a case report and review of the literature.

PubMed

Elhennawy, Karim; Reda, Seif; Finke, Christian; Graul-Neumann, Luitgard; Jost-Brinkmann, Paul-Georg; Bartzela, Theodosia

2017-08-15

Hereditary sensory and autonomic neuropathy type VIII is a rare autosomal recessive inherited disorder. Chen et al. recently identified the causative gene and characterized biallelic mutations in the PR domain-containing protein 12 gene, which plays a role in the development of pain-sensing nerve cells. Our patient's family was included in Chen and colleagues' study. We performed a literature review of the PubMed library (January 1985 to December 2016) on hereditary sensory and autonomic neuropathy type I to VIII genetic disorders and their orofacial manifestations. This case report is the first to describe the oral manifestations, and their treatment, of the recently discovered hereditary sensory and autonomic neuropathy type VIII in the medical and dental literature. We report on the oral manifestations and dental management of an 8-month-old white boy with hereditary sensory and autonomic neuropathy-VIII over a period of 16 years. Our patient was homozygous for a mutation of PR domain-containing protein 12 gene and was characterized by insensitivity to pain and thermal stimuli, self-mutilation behavior, reduced sweat and tear production, absence of corneal reflexes, and multiple skin and bone infections. Oral manifestations included premature loss of teeth, associated with dental traumata and self-mutilation, severe soft tissue injuries, dental caries and submucosal abscesses, hypomineralization of primary teeth, and mandibular osteomyelitis. The lack of scientific knowledge on hereditary sensory and autonomic neuropathy due to the rarity of the disease often results in a delay in diagnosis, which is of substantial importance for the prevention of many complications and symptoms. Interdisciplinary work of specialized medical and dental teams and development of a standardized treatment protocols are essential for the management of the disease. There are many knowledge gaps concerning the management of patients with hereditary sensory and autonomic neuropathy-VIII, therefore more research on an international basis is needed.

The metabolomic signature of Leber's hereditary optic neuropathy reveals endoplasmic reticulum stress.

PubMed

Chao de la Barca, Juan Manuel; Simard, Gilles; Amati-Bonneau, Patrizia; Safiedeen, Zainab; Prunier-Mirebeau, Delphine; Chupin, Stéphanie; Gadras, Cédric; Tessier, Lydie; Gueguen, Naïg; Chevrollier, Arnaud; Desquiret-Dumas, Valérie; Ferré, Marc; Bris, Céline; Kouassi Nzoughet, Judith; Bocca, Cinzia; Leruez, Stéphanie; Verny, Christophe; Miléa, Dan; Bonneau, Dominique; Lenaers, Guy; Martinez, M Carmen; Procaccio, Vincent; Reynier, Pascal

2016-11-01

Leber's hereditary optic neuropathy (MIM#535000), the commonest mitochondrial DNA-related disease, is caused by mutations affecting mitochondrial complex I. The clinical expression of the disorder, usually occurring in young adults, is typically characterized by subacute, usually sequential, bilateral visual loss, resulting from the degeneration of retinal ganglion cells. As the precise action of mitochondrial DNA mutations on the overall cell metabolism in Leber's hereditary optic neuropathy is unknown, we investigated the metabolomic profile of the disease. High performance liquid chromatography coupled with tandem mass spectrometry was used to quantify 188 metabolites in fibroblasts from 16 patients with Leber's hereditary optic neuropathy and eight healthy control subjects. Latent variable-based statistical methods were used to identify discriminating metabolites. One hundred and twenty-four of the metabolites were considered to be accurately quantified. A supervised orthogonal partial least squares discriminant analysis model separating patients with Leber's hereditary optic neuropathy from control subjects showed good predictive capability (Q 2cumulated = 0.57). Thirty-eight metabolites appeared to be the most significant variables, defining a Leber's hereditary optic neuropathy metabolic signature that revealed decreased concentrations of all proteinogenic amino acids, spermidine, putrescine, isovaleryl-carnitine, propionyl-carnitine and five sphingomyelin species, together with increased concentrations of 10 phosphatidylcholine species. This signature was not reproduced by the inhibition of complex I with rotenone or piericidin A in control fibroblasts. The importance of sphingomyelins and phosphatidylcholines in the Leber's hereditary optic neuropathy signature, together with the decreased amino acid pool, suggested an involvement of the endoplasmic reticulum. This was confirmed by the significantly increased phosphorylation of PERK and eIF2α, as well as the greater expression of C/EBP homologous protein and the increased XBP1 splicing, in fibroblasts from affected patients, all these changes being reversed by the endoplasmic reticulum stress inhibitor, TUDCA (tauroursodeoxycholic acid). Thus, our metabolomic analysis reveals a pharmacologically-reversible endoplasmic reticulum stress in complex I-related Leber's hereditary optic neuropathy fibroblasts, a finding that may open up new therapeutic perspectives for the treatment of Leber's hereditary optic neuropathy with endoplasmic reticulum-targeting drugs. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Friedreich's ataxia mimicking hereditary motor and sensory neuropathy.

PubMed

Panas, Marios; Kalfakis, Nikolaos; Karadima, Georgia; Davaki, Panagiota; Vassilopoulos, Demetris

2002-11-01

Four patients from three unrelated families, with clinical and electrophysiological findings compatible with the diagnosis of hereditary motor and sensory neuropathy, are presented. The molecular analysis showed that the affected individuals were homozygous for the mutation in the X25 gene, characteristic of Friedreich's ataxia. These patients seem to represent a form of Friedreich's ataxia mimicking Charcot-Marie-Tooth disease.

[Evaluation of fundus autofluorescence in hereditary retinal diseases using Heidelberg Retina Angiograph2].

PubMed

Côco, Monique; Baba, Natalia Tamie; Sallum, Juliana Maria Ferraz

2007-01-01

To define characteristics of the fundus autofluorescence examination, verifying usefulness in the diagnosis and care of hereditary retinal diseases. 28 patients, adults, divided equally into four groups with diagnoses of Stargardt macular dystrophy, cone dystrophy, retinitis pigmentosa and healthy volunteers for the establishment of the normality pattern. An average of nine images with the filter for fluorescein angiography was obtained for the formation of the image autofluorescence using Heidelberg Retina Angiograph2. The images of each group of patients were analyzed to verify common characteristics. The fundus autofluorescence of healthy volunteers showed the foveal area darker than the surrounding retina. The images of Stargardt macular dystrophy, in general, presented an oval central lesion, with reduced autofluorescence. The main alterations of the autofluorescence in patients with cone dystrophy were reduced foveal autofluorescence with a parafoveal ring of increased autofluorescence. In general, the images of retinitis pigmentosa showed outlying pigments with reduced autofluorescence, and of the foveal area, in some cases disorganization or reduced autofluorescence. The study showed the existence of patterns of fundus autofluorescence in the hereditary retinal diseases that allow the diagnosis and better interpretation of the pathogenesis of these diseases.

Developing an item bank to measure the coping strategies of people with hereditary retinal diseases.

PubMed

Prem Senthil, Mallika; Khadka, Jyoti; De Roach, John; Lamey, Tina; McLaren, Terri; Campbell, Isabella; Fenwick, Eva K; Lamoureux, Ecosse L; Pesudovs, Konrad

2018-05-05

Our understanding of the coping strategies used by people with visual impairment to manage stress related to visual loss is limited. This study aims to develop a sophisticated coping instrument in the form of an item bank implemented via Computerised adaptive testing (CAT) for hereditary retinal diseases. Items on coping were extracted from qualitative interviews with patients which were supplemented by items from a literature review. A systematic multi-stage process of item refinement was carried out followed by expert panel discussion and cognitive interviews. The final coping item bank had 30 items. Rasch analysis was used to assess the psychometric properties. A CAT simulation was carried out to estimate an average number of items required to gain precise measurement of hereditary retinal disease-related coping. One hundred eighty-nine participants answered the coping item bank (median age = 58 years). The coping scale demonstrated good precision and targeting. The standardised residual loadings for items revealed six items grouped together. Removal of the six items reduced the precision of the main coping scale and worsened the variance explained by the measure. Therefore, the six items were retained within the main scale. Our CAT simulation indicated that, on average, less than 10 items are required to gain a precise measurement of coping. This is the first study to develop a psychometrically robust coping instrument for hereditary retinal diseases. CAT simulation indicated that on an average, only four and nine items were required to gain measurement at moderate and high precision, respectively.

Microvascular Pathology and Morphometrics of Sporadic and Hereditary Small Vessel Diseases of the Brain

PubMed Central

Craggs, Lucinda JL; Yamamoto, Yumi; Deramecourt, Vincent; Kalaria, Raj N

2014-01-01

Small vessel diseases (SVDs) of the brain are likely to become increasingly common in tandem with the rise in the aging population. In recent years, neuroimaging and pathological studies have informed on the pathogenesis of sporadic SVD and several single gene (monogenic) disorders predisposing to subcortical strokes and diffuse white matter disease. However, one of the limitations toward studying SVD lies in the lack of consistent assessment criteria and lesion burden for both clinical and pathological measures. Arteriolosclerosis and diffuse white matter changes are the hallmark features of both sporadic and hereditary SVDs. The pathogenesis of the arteriopathy is the key to understanding the differential progression of disease in various SVDs. Remarkably, quantification of microvascular abnormalities in sporadic and hereditary SVDs has shown that qualitatively the processes involved in arteriolar degeneration are largely similar in sporadic SVD compared with hereditary disorders such as cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Important significant regional differences in lesion location within the brain may enable one to distinguish SVDs, where frontal lobe involvement appears consistently with almost every SVD, but others bear specific pathologies in other lobes, such as the temporal pole in CADASIL and the pons in pontine autosomal dominant microangiopathy and leukoencephalopathy or PADMAL. Additionally, degenerative changes in the vascular smooth muscle cells, the cerebral endothelium and the basal lamina are often rapid and more aggressive in genetic disorders. Further quantification of other microvascular elements and even neuronal cells is needed to fully characterize SVD pathogenesis and to differentiate the usefulness of vascular interventions and treatments on the resulting pathology. PMID:25323665

Bevacizumab as a treatment for hereditary hemorrhagic telangiectasia in children: a case report

PubMed Central

Ospina, Fabio E; Echeverri, Alex; Posso-Osorio, Iván; Jaimes, Lina; Gutierrez, Jaiber

2017-01-01

Abstract Case description: Five-year-old female patient with hereditary hemorrhagic telangiectasia. Clinical Findings: Deterioration of cardiopulmonary function with higher oxygen requirements secondary to pulmonary arteriovenous shunts, epistaxis. Treatment and Outcome: The patient was treated with the monoclonal antibody bevacizumab, which inhibits the vascular endothelial growth factor, with good clinical outcome. Clinical Relevance: Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by arteriovenous malformations in different organs, making its clinical presentations varied. Systemic therapeutic options for a generalized disease are limited. The monoclonal antibody bevacizumab, seems to be a good option in this disorder. Although reported as successful in adult population, its use in pediatric population has not yet been reported. Here we report the use of bevacizumab in a 5-year-old female patient with hereditary hemorrhagic telangiectasia, showing clinical benefits and good outcome. PMID:29021642

An Up-to-date Approach to a Patient with a Suspected Autoinflammatory Disease

PubMed Central

Lidar, Merav; Giat, Eitan

2017-01-01

Autoinflammatory diseases (AID) are characterized by seemingly unprovoked self-limited attacks of fever and systemic inflammation potentially leading to amyloidosis. Familial Mediterranean fever (FMF) is the most common AID and therefore the most studied. Besides FMF, the other main hereditary AID are tumor necrosis factor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD), and cryopyrin-associated periodic fever syndrome (CAPS). These hereditary diseases result from a mutant gene that is involved in the regulation of inflammation, resulting in a characteristic clinical phenotype. The differential diagnosis of AID can be challenging due to a wide overlap in clinical manifestations. Moreover, a considerable proportion of patients present with autoinflammatory symptoms but without a pathogenetic variant on genetic analysis. Furthermore, non-hereditary AID, such as the periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome, which is the most common AID in children worldwide, must be excluded in certain circumstances. Herein we shall review the main AID and describe a practical approach to diagnosis in a patient with a clinical suspicion of AID. PMID:28178435

Stem Cell Ophthalmology Treatment Study (SCOTS): bone marrow-derived stem cells in the treatment of Leber's hereditary optic neuropathy

PubMed Central

Weiss, Jeffrey N.; Levy, Steven; Benes, Susan C.

2016-01-01

The Stem Cell Ophthalmology Treatment Study (SCOTS) is currently the largest-scale stem cell ophthalmology trial registered at ClinicalTrials.gov (identifier: NCT01920867). SCOTS utilizes autologous bone marrow-derived stem cells (BMSCs) to treat optic nerve and retinal diseases. Treatment approaches include a combination of retrobulbar, subtenon, intravitreal, intra-optic nerve, subretinal, and intravenous injection of autologous BMSCs according to the nature of the disease, the degree of visual loss, and any risk factors related to the treatments. Patients with Leber's hereditary optic neuropathy had visual acuity gains on the Early Treatment Diabetic Retinopathy Study (ETDRS) of up to 35 letters and Snellen acuity improvements from hand motion to 20/200 and from counting fingers to 20/100. Visual field improvements were noted. Macular and optic nerve head nerve fiber layer typically thickened. No serious complications were seen. The increases in visual acuity obtained in our study were encouraging and suggest that the use of autologous BMSCs as provided in SCOTS for ophthalmologic mitochondrial diseases including Leber's hereditary optic neuropathy may be a viable treatment option. PMID:27904503

Pregnancy and mesenchimal dysplasias (Marfan syndrome, Ehlers-Danlos syndrome, hereditary hemorrhagic telangiectasia).

PubMed

Radetskaya, L S; Makatsariya, A D; Bitsadze, V O; Khizroeva, J K

2018-07-01

The objective of this article is to attract the attention of clinical physicians to the rare but extremely relevant clinical pathology of mesenchymal dysplasias (Marfan syndrome, Ehlers-Danlos syndrome, hereditary hemorrhagic telangiectasia) and especially specific characteristics of such diseases during pregnancy. Connective tissue pathology can cover different organs and systems, symptoms of the same disease can vary in different patients thus making diagnostics significantly difficult. Here clinical diagnostic criteria and methods of molecular diagnostics of diseases are described. The pathogenesis of mesenchymal dysplasias is not currently well understood. For the patients with mesenchymal dysplasias pregnancy is fraught with high risk of life-threatening complications. The preferred delivery method for such patients is caesarean section.

Type I hereditary punctate keratoderma.

PubMed

Asadi, Arash K

2003-10-01

A 75-year-old man with a history of prostatic carcinoma and atypical fibroxanthoma reports a long-standing history of 1-2 mm depressed, hyperkeratotic papules on the palms. His mother suffered a similar condition. Histologically, the papules demonstrated hyperkeratosis, without columns of parakeratosis. A diagnosis of type I hereditary punctate keratoderma (Buschke-Fisher-Brauer disease) was made. This condition, which is classified as one of the three hereditary forms of punctate palmoplantar keratoderma, is an autosomal-dominant condition with variable penetrance. It is characterized clinically by multiple, tiny, punctate keratoses of the palms and soles. Affected individuals appear to be at increased risk of developing malignant conditions.

What Is Crohn's Disease?

MedlinePlus

... own. Recent research suggests hereditary, genetics, and/or environmental factors contribute to the development of Crohn’s Disease. The GI tract normally contains harmless bacteria, many of which aid in digestion. The immune ...

Stem Cell Ophthalmology Treatment Study II

ClinicalTrials.gov

2018-02-01

Retinal Disease; Age-Related Macular Degeneration; Retinitis Pigmentosa; Stargardt Disease; Optic Neuropathy; Nonarteritic Ischemic Optic Neuropathy; Optic Atrophy; Optic Nerve Disease; Glaucoma; Leber Hereditary Optic Neuropathy; Blindness; Vision Loss Night; Vision Loss Partial; Vision, Low; Retinopathy; Maculopathy; Macular Degeneration; Retina Atrophy

Exuberant clinical picture of Buschke-Fischer-Brauer palmoplantar keratoderma in bedridden patient.

PubMed

Antonio, João Roberto; Oliveira, Guilherme Bueno de; Rossi, Natalia Cristina Pires; Pires, Laiza Gabriela Garcia

2014-01-01

Buschke-Fisher-Brauer keratoderma is a rare hereditary autosomal dominant disease of incomplete penetrance. Important differential diagnoses include other palmoplantar keratinization disorders, acquired or hereditary, which is done based on the histopathological findings. This diagnosis alerts especially about the possibility of associated neoplasms. Treatment involves topical keratolytic agents, usually with little efficacy, or with long-term systemic retinoids with follow-up of exuberant collateral effects.

Genetic heterogeneity of motor neuropathies

PubMed Central

Bansagi, Boglarka; Griffin, Helen; Whittaker, Roger G.; Antoniadi, Thalia; Evangelista, Teresinha; Miller, James; Greenslade, Mark; Forester, Natalie; Duff, Jennifer; Bradshaw, Anna; Kleinle, Stephanie; Boczonadi, Veronika; Steele, Hannah; Ramesh, Venkateswaran; Franko, Edit; Pyle, Angela; Lochmüller, Hanns; Chinnery, Patrick F.

2017-01-01

Objective: To study the prevalence, molecular cause, and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the North of England. Methods: Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex neurologic disease predominantly affecting the motor nerves (hereditary motor neuropathy plus, 25 patients). Results: The prevalence of dHMN is 2.14 affected individuals per 100,000 inhabitants (95% confidence interval 1.62–2.66) in the North of England. Causative mutations were identified in 26 out of 73 index patients (35.6%). The diagnostic rate in the dHMN subgroup was 32.5%, which is higher than previously reported (20%). We detected a significant defect of neuromuscular transmission in 7 cases and identified potentially causative mutations in 4 patients with multifocal demyelinating motor neuropathy. Conclusions: Many of the genes were shared between dHMN and motor CMT2, indicating identical disease mechanisms; therefore, we suggest changing the classification and including dHMN also as a subcategory of Charcot-Marie-Tooth disease. Abnormal neuromuscular transmission in some genetic forms provides a treatable target to develop therapies. PMID:28251916

Loss-of-function mutations in the ATP13A2/PARK9 gene cause complicated hereditary spastic paraplegia (SPG78)

PubMed Central

Estrada-Cuzcano, Alejandro; Martin, Shaun; Chamova, Teodora; Synofzik, Matthis; Timmann, Dagmar; Holemans, Tine; Andreeva, Albena; Reichbauer, Jennifer; De Rycke, Riet; Chang, Dae-In; van Veen, Sarah; Samuel, Jean; Schöls, Ludger; Pöppel, Thorsten; Mollerup Sørensen, Danny; Asselbergh, Bob; Klein, Christine; Zuchner, Stephan; Jordanova, Albena; Vangheluwe, Peter; Tournev, Ivailo; Schüle, Rebecca

2017-01-01

Abstract Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders characterized by progressive spasticity of the lower limbs due to degeneration of the corticospinal motor neurons. In a Bulgarian family with three siblings affected by complicated hereditary spastic paraplegia, we performed whole exome sequencing and homozygosity mapping and identified a homozygous p.Thr512Ile (c.1535C > T) mutation in ATP13A2. Molecular defects in this gene have been causally associated with Kufor-Rakeb syndrome (#606693), an autosomal recessive form of juvenile-onset parkinsonism, and neuronal ceroid lipofuscinosis (#606693), a neurodegenerative disorder characterized by the intracellular accumulation of autofluorescent lipopigments. Further analysis of 795 index cases with hereditary spastic paraplegia and related disorders revealed two additional families carrying truncating biallelic mutations in ATP13A2. ATP13A2 is a lysosomal P5-type transport ATPase, the activity of which critically depends on catalytic autophosphorylation. Our biochemical and immunocytochemical experiments in COS-1 and HeLa cells and patient-derived fibroblasts demonstrated that the hereditary spastic paraplegia-associated mutations, similarly to the ones causing Kufor-Rakeb syndrome and neuronal ceroid lipofuscinosis, cause loss of ATP13A2 function due to transcript or protein instability and abnormal intracellular localization of the mutant proteins, ultimately impairing the lysosomal and mitochondrial function. Moreover, we provide the first biochemical evidence that disease-causing mutations can affect the catalytic autophosphorylation activity of ATP13A2. Our study adds complicated hereditary spastic paraplegia (SPG78) to the clinical continuum of ATP13A2-associated neurological disorders, which are commonly hallmarked by lysosomal and mitochondrial dysfunction. The disease presentation in our patients with hereditary spastic paraplegia was dominated by an adult-onset lower-limb predominant spastic paraparesis. Cognitive impairment was present in most of the cases and ranged from very mild deficits to advanced dementia with fronto-temporal characteristics. Nerve conduction studies revealed involvement of the peripheral motor and sensory nerves. Only one of five patients with hereditary spastic paraplegia showed clinical indication of extrapyramidal involvement in the form of subtle bradykinesia and slight resting tremor. Neuroimaging cranial investigations revealed pronounced vermian and hemispheric cerebellar atrophy. Notably, reduced striatal dopamine was apparent in the brain of one of the patients, who had no clinical signs or symptoms of extrapyramidal involvement. PMID:28137957

Preliminary investigation of bottlenose dolphins (Tursiops truncatus) for hfe gene-related hemochromatosis.

PubMed

Phillips, Brianne E; Venn-Watson, Stephanie; Archer, Linda L; Nollens, Hendrik H; Wellehan, James F X

2014-10-01

Hemochromatosis (iron storage disease) has been reported in diverse mammals including bottlenose dolphins (Tursiops truncatus). The primary cause of excessive iron storage in humans is hereditary hemochromatosis. Most human hereditary hemochromatosis cases (up to 90%) are caused by a point mutation in the hfe gene, resulting in a C282Y substitution leading to iron accumulation. To evaluate the possibility of a hereditary hemochromatosis-like genetic predisposition in dolphins, we sequenced the bottlenose dolphin hfe gene, using reverse transcriptase-PCR and hfe primers designed from the dolphin genome, from liver of affected and healthy control dolphins. Sample size included two case animals and five control animals. Although isotype diversity was evident, no coding differences were identified in the hfe gene between any of the animals examined. Because our sample size was small, we cannot exclude the possibility that hemochromatosis in dolphins is due to a coding mutation in the hfe gene. Other potential causes of hemochromatosis, including mutations in different genes, diet, primary liver disease, and insulin resistance, should be evaluated.

Epigenetics and genetics in endometrial cancer: new carcinogenic mechanisms and relationship with clinical practice.

PubMed

Banno, Kouji; Kisu, Iori; Yanokura, Megumi; Masuda, Kenta; Ueki, Arisa; Kobayashi, Yusuke; Susumu, Nobuyuki; Aoki, Daisuke

2012-04-01

Endometrial cancer is the seventh most common cancer worldwide among females. An increased incidence and a younger age of patients are also predicted to occur, and therefore elucidation of the pathological mechanisms is important. However, several aspects of the mechanism of carcinogenesis in the endometrium remain unclear. Associations with genetic mutations of cancer-related genes have been shown, but these do not provide a complete explanation. Therefore, epigenetic mechanisms have been examined. Silencing of genes by DNA hypermethylation, hereditary epimutation of DNA mismatch repair genes and regulation of gene expression by miRNAs may underlie carcinogenesis in endometrial cancer. New therapies include targeting epigenetic changes using histone deacetylase inhibitors. Some cases of endometrial cancer may also be hereditary. Thus, patients with Lynch syndrome which is a hereditary disease, have a higher risk for developing endometrial cancer than the general population. Identification of such disease-related genes may contribute to early detection and prevention of endometrial cancer.

Genetic spectrum of hereditary neuropathies with onset in the first year of life

PubMed Central

Baets, Jonathan; Deconinck, Tine; De Vriendt, Els; Zimoń, Magdalena; Yperzeele, Laetitia; Van Hoorenbeeck, Kim; Peeters, Kristien; Spiegel, Ronen; Parman, Yesim; Ceulemans, Berten; Van Bogaert, Patrick; Pou-Serradell, Adolf; Bernert, Günther; Dinopoulos, Argirios; Auer-Grumbach, Michaela; Sallinen, Satu-Leena; Fabrizi, Gian Maria; Pauly, Fernand; Van den Bergh, Peter; Bilir, Birdal; Battaloglu, Esra; Madrid, Ricardo E.; Kabzińska, Dagmara; Kochanski, Andrzej; Topaloglu, Haluk; Miller, Geoffrey; Jordanova, Albena; Timmerman, Vincent

2011-01-01

Early onset hereditary motor and sensory neuropathies are rare disorders encompassing congenital hypomyelinating neuropathy with disease onset in the direct post-natal period and Dejerine–Sottas neuropathy starting in infancy. The clinical spectrum, however, reaches beyond the boundaries of these two historically defined disease entities. De novo dominant mutations in PMP22, MPZ and EGR2 are known to be a typical cause of very early onset hereditary neuropathies. In addition, mutations in several other dominant and recessive genes for Charcot–Marie–Tooth disease may lead to similar phenotypes. To estimate mutation frequencies and to gain detailed insights into the genetic and phenotypic heterogeneity of early onset hereditary neuropathies, we selected a heterogeneous cohort of 77 unrelated patients who presented with symptoms of peripheral neuropathy within the first year of life. The majority of these patients were isolated in their family. We performed systematic mutation screening by means of direct sequencing of the coding regions of 11 genes: MFN2, PMP22, MPZ, EGR2, GDAP1, NEFL, FGD4, MTMR2, PRX, SBF2 and SH3TC2. In addition, screening for the Charcot–Marie–Tooth type 1A duplication on chromosome 17p11.2-12 was performed. In 35 patients (45%), mutations were identified. Mutations in MPZ, PMP22 and EGR2 were found most frequently in patients presenting with early hypotonia and breathing difficulties. The recessive genes FGD4, PRX, MTMR2, SBF2, SH3TC2 and GDAP1 were mutated in patients presenting with early foot deformities and variable delay in motor milestones after an uneventful neonatal period. Several patients displaying congenital foot deformities but an otherwise normal early development carried the Charcot–Marie–Tooth type 1A duplication. This study clearly illustrates the genetic heterogeneity underlying hereditary neuropathies with infantile onset. PMID:21840889

Newly designed 11-gene panel reveals first case of hereditary amyloidosis captured by massive parallel sequencing.

PubMed

Chyra Kufova, Zuzana; Sevcikova, Tereza; Januska, Jaroslav; Vojta, Petr; Boday, Arpad; Vanickova, Pavla; Filipova, Jana; Growkova, Katerina; Jelinek, Tomas; Hajduch, Marian; Hajek, Roman

2018-02-17

Amyloidosis is caused by deposition of abnormal protein fibrils, leading to damage of organ function. Hereditary amyloidosis represents a monogenic disease caused by germline mutations in 11 amyloidogenic precursor protein genes. One of the important but non-specific symptoms of amyloidosis is hypertrophic cardiomyopathy. Diagnostics of hereditary amyloidosis is complicated and the real cause can remain overlooked. We aimed to design hereditary amyloidosis gene panel and to introduce new next-generation sequencing (NGS) approach to investigate hereditary amyloidosis in a cohort of patients with hypertrophic cardiomyopathy of unknown significance. Design of target enrichment DNA library preparation using Haloplex Custom Kit containing 11 amyloidogenic genes was followed by MiSeq Illumina sequencing and bioinformatics identification of germline variants using tool VarScan in a cohort of 40 patients. We present design of NGS panel for 11 genes ( TTR , FGA , APOA1 , APOA2 , LYZ , GSN , CST3 , PRNP , APP , B2M , ITM2B ) connected to various forms of amyloidosis. We detected one mutation, which is responsible for hereditary amyloidosis. Some other single nucleotide variants are so far undescribed or rare variants or represent common polymorphisms in European population. We report one positive case of hereditary amyloidosis in a cohort of patients with hypertrophic cardiomyopathy of unknown significance and set up first panel for NGS in hereditary amyloidosis. This work may facilitate successful implementation of the NGS method by other researchers or clinicians and may improve the diagnostic process after validation. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

[Involuntary sterilization of men in the Third Reich using the example of the surgical clinic in Göttingen from 1934-1944].

PubMed

Hansson, N

2015-04-01

The German Law for Prevention of Genetically Diseased Offspring (Das Gesetz zur Verhütung erbkranken Nachwuchses) was enacted in 1933. It allowed forced sterilization of patients who had been diagnosed with certain so-called hereditary diseases. Drawing on patient files from the city of Göttingen, this article provides new research results about the practice of forced sterilization of men in the Third Reich. Results show that around 1000 men were sentenced to sterilization by the local hereditary health court (Erbgesundheitsgericht). In this article, some aspects of the operation and "refertilization" are reconstructed.

Severe jaundice due to coexistence of Dubin-Johnson syndrome and hereditary spherocytosis: a case report.

PubMed

Korkmaz, Uğur; Duman, Ali Erkan; Oğütmen Koç, Deniz; Gürbüz, Yeşim; Dındar, Gökhan; Ensaroğlu, Fatih; Sener, Selçuk Yusuf; Sentürk, Omer; Hülagü, Sadettin

2011-08-01

Dubin-Johnson syndrome is a chronic, benign, intermittent jaundice, mostly of conjugated hyperbilirubinemia. The level of bilirubin is not expected to be more than 20 mg/dl in this syndrome. In this article, we report a patient who was evaluated for hyperbilirubinemia and liver function test abnormalities and diagnosed with Dubin-Johnson syndrome coexisting with hereditary spherocytosis. We suggest that other diseases should be investigated if patients with Dubin-Johnson syndrome present with severe hyperbilirubinemia. Dubin-Johnson syndrome accompanied by hemolytic diseases might also have high coproporphyrin levels (as in Rotor's syndrome) than expected in pure Dubin-Johnson syndrome.

[Treatment of hereditary angioedema].

PubMed

Qian, X

1990-06-01

Hereditary angioedema is a rare familial disease caused by the defect of complement C1esterase inhibitor (C1-INH). It is characterized by recurrent acute edema of the extremities, the face, the respiratory tract and the gastrointestinal tract. Acute laryngeal edema usually produces laryngeal obstruction. Two cases have been treated since 1986, one of them had been admitted for forty-five times because of recurrent acute laryngeal edema. Investigations showed two families with a high incidence of this disease. Laboratory examination showed a remarkable decrease of C1-INH and C4. Tracheotomy is indicated in patients with laryngeal edema. Great success was achieved in two patients treated with danazol.

Diagnosing the dead: the retrospective analysis of genetic diseases.

PubMed

Rushton, A R

2013-01-01

The suspected presence of hereditary disease in important historical and political figures has interested researchers for many decades. Whether Abraham Lincoln suffered from Marfan syndrome, if George III became 'mad' because he inherited variegate porphyria, and if the Romanov dynasty collapsed because the heir Alexei inherited haemophilia are important questions; physical illness can adversely affect the ability of leaders to function within the social and political realm of their day. This article will outline an approach to such a medical-historical analysis including assessment of hereditary predisposition, family history and the use of DNA technology to confirm or deny the clinical suspicions of the investigator.

MMACHC gene mutation in familial hypogonadism with neurological symptoms.

PubMed

Shi, Changhe; Shang, Dandan; Sun, Shilei; Mao, Chengyuan; Qin, Jie; Luo, Haiyang; Shao, Mingwei; Chen, Zhengguang; Liu, Yutao; Liu, Xinjing; Song, Bo; Xu, Yuming

2015-12-15

Recent studies have convincingly documented that hypogonadism is a component of various hereditary disorders and is often recognized as an important clinical feature in combination with various neurological symptoms, yet, the causative genes in a few related families are still unknown. High-throughput sequencing has become an efficient method to identify causative genes in related complex hereditary disorders. In this study, we performed exome sequencing in a family presenting hypergonadotropic hypogonadism with neurological presentations of mental retardation, epilepsy, ataxia, and leukodystrophy. After bioinformatic analysis and Sanger sequencing validation, we identified compound heterozygous mutations: c.482G>A (p.R161Q) and c.609G>A (p.W203X) in MMACHC gene in this pedigree. MMACHC was previously confirmed to be responsible for methylmalonic aciduria (MMA) combined with homocystinuria, cblC type (cblC disease), a hereditary vitamin B12 metabolic disorder. Biochemical and gas chromatography-mass spectrometry (GC-MS) examinations in this pedigree further supported the cblC disease diagnosis. These results indicated that hypergonadotropic hypogonadism may be a novel clinical manifestation of cblC disease, but more reports on additional patients are needed to support this hypothesis. Copyright © 2015 Elsevier B.V. All rights reserved.

Reply [to “Comment on ‘Norwegians led the way in training wartime weather officers’”

NASA Astrophysics Data System (ADS)

Levin, Sheldon

I appreciate the acknowledgment of my article and note the discrepancies that were mentioned. The legacy in science of the Bjerknes family was mentioned when I was a student in 1942. C. Bjerknes, who worked with Helmholz, his son, V. Bjerknes, and then, of course, Jakob. I did not know much at that time of the importance of Jakob's father. After my article was printed, I learned of a superb book about V. Bjerknes, Appropriating the Weather, by Robert Marc Friedman.

How the shapes of seeds can influence pathology.

PubMed

Melki, Ronald

2018-01-01

It is widely accepted that the loss of function of different cellular proteins following their aggregation into highly stable aggregates or the gain of pathologic function of the resulting macromolecular assemblies or both processes are tightly associated to distinct debilitating neurodegenerative diseases such as Alzheimer's, Parkinson's, Creutzfeldt-Jacob, Amyotrophic Lateral Sclerosis and Huntington's diseases. How the aggregation of one given protein leads to distinct diseases is unclear. Here, a structural-molecular explanation based on the ability of proteins such as α-synuclein or tau to form assemblies that differ by their intrinsic architecture, stability, seeding capacity, and surfaces is proposed to account for distinct synucleinopathies and tauopathies. The shape and surfaces of the seeds is proposed to define at the same time their seeding capacity, interactome and tropism for defined neuronal cells within the central nervous system. Copyright © 2017 Elsevier Inc. All rights reserved.

Familial pyrophosphate arthropathy. Occurrence and Crystal Identification.

PubMed

Bjelle, A

1981-01-01

Hereditary pyrophosphate arthropathy has been observed in three Swedish families and in a few other caucasian populations. The inheritance is most probably autosomal dominant with a variable penetrance. The most severe cases have been found in homozygotes among isolates of immigrants in Slovakia and Chile. Studies on genetic and etio-pathogenetic factors in hereditary pyrophosphate arthropathy, and the utilization of new diagnostic techniques for crystal identification, are important approaches towards a further understanding of the disease.

HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum.

PubMed

Gess, Burkhard; Auer-Grumbach, Michaela; Schirmacher, Anja; Strom, Tim; Zitzelsberger, Manuela; Rudnik-Schöneborn, Sabine; Röhr, Dominik; Halfter, Hartmut; Young, Peter; Senderek, Jan

2014-11-04

To determine the nature and frequency of HSJ1 mutations in patients with hereditary motor and hereditary motor and sensory neuropathies. Patients were screened for mutations by genome-wide or targeted linkage and homozygosity studies, whole-exome sequencing, and Sanger sequencing. RNA and protein studies of skin fibroblasts were used for functional characterization. We describe 2 additional mutations in the HSJ1 gene in a cohort of 90 patients with autosomal recessive distal hereditary motor neuropathy (dHMN) and Charcot-Marie-Tooth disease type 2 (CMT2). One family with a dHMN phenotype showed the homozygous splice-site mutation c.229+1G>A, which leads to retention of intron 4 in the HSJ1 messenger RNA with a premature stop codon and loss of protein expression. Another family, presenting with a CMT2 phenotype, carried the homozygous missense mutation c.14A>G (p.Tyr5Cys). This mutation was classified as likely disease-related by several automatic algorithms for prediction of possible impact of an amino acid substitution on the structure and function of proteins. Both mutations cosegregated with autosomal recessive inheritance of the disease and were absent from the general population. Taken together, in our cohort of 90 probands, we confirm that HSJ1 mutations are a rare but detectable cause of autosomal recessive dHMN and CMT2. We provide clinical and functional information on an HSJ1 splice-site mutation and report the detailed phenotype of 2 patients with CMT2, broadening the phenotypic spectrum of HSJ1-related neuropathies. © 2014 American Academy of Neurology.

Treatment for Patients With Malignant Pheochromocytomas and Paragangliomas: A Perspective From the Hallmarks of Cancer

PubMed Central

Jimenez, Camilo

2018-01-01

Malignant pheochromocytomas and paragangliomas affect a very small percentage of the general population. A substantial number of these patients have a hereditary predisposition for the disease and consequently, bear the risk of developing these tumors throughout their entire lives. It is, however, unclear why some patients with no hereditary predisposition develop these tumors, which frequently share a similar molecular phenotype with their hereditary counterparts. Both hereditary and sporadic tumors usually appear at an early age, and affected people often die before reaching their expected lifespans. Unfortunately, there is currently no systemic therapy approved for patients with this orphan disease. Therefore, pheochromocytomas and paragangliomas are very challenging malignancies. The recognition of genetic and molecular abnormalities responsible for the development of these tumors as well as the identification of effective therapies for other malignancies that share a similar pathogenesis is leading to the development of exciting clinical trials. Tyrosine kinase inhibitors, radiopharmaceutical agents, and immunotherapy are currently under evaluation in prospective clinical trials. A phase 2 clinical trial of the highly specific metaiodobenzylguanidine, iobenguane 131I, has provided impressive results; this radiopharmaceutical agent may become the first approved systemic therapy for patients with malignant pheochromocytoma and paraganglioma by the United States Food and Drug Administration. Nevertheless, systemic therapies are still not able to cure the disease. This review will discuss the development of systemic therapeutic approaches using the hallmarks of cancer as a framework. This approach will help the reader to understand where research efforts currently stand and what the future for this difficult field may be.

The psychological complexity of predictive testing for late onset neurogenetic diseases and hereditary cancers: implications for multidisciplinary counselling and for genetic education.

PubMed

Evers-Kiebooms, G; Welkenhuysen, M; Claes, E; Decruyenaere, M; Denayer, L

2000-09-01

Increasing knowledge about the human genome has resulted in the availability of a steadily increasing number of predictive DNA-tests for two major categories of diseases: neurogenetic diseases and hereditary cancers. The psychological complexity of predictive testing for these late onset diseases requires careful consideration. It is the main aim of the present paper to describe this psychological complexity, which necessitates an adequate and systematic multidisciplinary approach, including psychological counselling, as well as ongoing education of professionals and of the general public. Predictive testing for neurogenetic diseases--in an adequate counselling context--so far elicits optimism regarding the short- and mid-term impact of the predictive test result. The psychosocial impact has been most widely studied for Huntington's disease. Longitudinal studies are of the utmost importance in evaluating the long-term impact of predictive testing for neurogenetic diseases on the tested person and his/her family. Given the more recent experience with predictive DNA-testing for hereditary cancers, fewer published scientific data are available. Longitudinal research on the mid- and long-term psychological impact of the predictive test result is essential. Decision making regarding health surveillance or preventive surgery after being detected as a carrier of one of the relevant mutations should receive special attention. Tailoring the professional approach--inside and outside genetic centres--to the families' needs is a continuous challenge. Even if a continuous effort is made, several important questions remain unanswered, last but not least the question regarding the best strategy to guarantee that the availability of predictive genetic testing results in a reduction of suffering caused by genetic disease and in an improvement of the quality of life of families confronted with genetic disease.

HFE gene in primary and secondary hepatic iron overload

PubMed Central

Sebastiani, Giada; Walker, Ann P

2007-01-01

Distinct from hereditary haemochromatosis, hepatic iron overload is a common finding in several chronic liver diseases. Many studies have investigated the prevalence, distribution and possible contributory role of excess hepatic iron in non-haemochromatotic chronic liver diseases. Indeed, some authors have proposed iron removal in liver diseases other than hereditary haemochromatosis. However, the pathogenesis of secondary iron overload remains unclear. The High Fe (HFE) gene has been implicated, but the reported data are controversial. In this article, we summarise current concepts regarding the cellular role of the HFE protein in iron homeostasis. We review the current status of the literature regarding the prevalence, hepatic distribution and possible therapeutic implications of iron overload in chronic hepatitis C, hepatitis B, alcoholic and non-alcoholic fatty liver diseases and porphyria cutanea tarda. We discuss the evidence regarding the role of HFE gene mutations in these liver diseases. Finally, we summarize the common and specific features of iron overload in liver diseases other than haemochromatosis. PMID:17729389

Hereditary Hemochromatosis Restores the Virulence of Plague Vaccine Strains

PubMed Central

Quenee, Lauriane E.; Hermanas, Timothy M.; Ciletti, Nancy; Louvel, Helene; Miller, Nathan C.; Elli, Derek; Blaylock, Bill; Mitchell, Anthony; Schroeder, Jay; Krausz, Thomas; Kanabrocki, Joseph; Schneewind, Olaf

2012-01-01

Nonpigmented Yersinia pestis (pgm) strains are defective in scavenging host iron and have been used in live-attenuated vaccines to combat plague epidemics. Recently, a Y. pestis pgm strain was isolated from a researcher with hereditary hemochromatosis who died from laboratory-acquired plague. We used hemojuvelin-knockout (Hjv−/−) mice to examine whether iron-storage disease restores the virulence defects of nonpigmented Y. pestis. Unlike wild-type mice, Hjv−/− mice developed lethal plague when challenged with Y. pestis pgm strains. Immunization of Hjv−/− mice with a subunit vaccine that blocks Y. pestis type III secretion generated protection against plague. Thus, individuals with hereditary hemochromatosis may be protected with subunit vaccines but should not be exposed to live-attenuated plague vaccines. PMID:22896664

Red cell 2,3-diphosphoglycerate levels in children with hereditary haemolytic anaemias.

PubMed

Haidas, S; Zannos-Mariolea, L; Matsaniotis, N

1975-12-01

The role of red cell 2,3-diphosphoglycerate (2,3-DPG) in increasing the availability of haemoglobin oxygen in neonatal jaundice and hereditary haemolytic anaemias was investigated. Measurements of 2,3-DPG were carried out on 58 normal children and six normal adults, 18 full-term newborns with neonatal jaundice and 57 cases (51 children and six adults) with hereditary haemolytic anaemias. In normal children and adults, with a mean haemoglobin of 12.69 g/dl, mean 2,3-DPG was 14.90 mumol/g Hb. In jaundiced newborns with a mean haemoglobin of 16.04 g/dl mean 2,3-DPG levels were 14.51 mumol/g Hb, i.e. normal. 2,3-DPG levels were increased in patients with beta-thalassaemia major, alpha-thalassaemia, sickle-cell disease, favism, hereditary spherocytosis and in heterozygotes for beta-thalassaemia with increased haemoglobin F. In heterozygotes for beta-thalassaemia with increased haemoglobin A2 only and in sickle cell trait 2,3-DPG levels were normal.

Alport syndrome

MedlinePlus

... deafness; Hemorrhagic familial nephritis; Hereditary deafness and nephropathy Images Male urinary system References Appel GB, Radhakrishnan J, D'Agati V. Secondary glomerular disease. In: Skorecki ...

Circular RNAs and hereditary bone diseases.

PubMed

Zhai, Naixiang; Lu, Yanqin; Wang, Yanzhou; Ren, Xiuzhi; Han, Jinxiang

2018-02-01

Circular RNA (circRNA) is a non-linear form of RNA derived from exonic, intronic, and exon-intron gene regions. circRNAs are characterized by covalent closed loops, highly stable nuclease resistance, and specific expression in species and developmental stages. CircRNA molecules have been identified as playing roles in the regulation of cell transcription, transcriptional expression after translation, interactions with microRNAs, and protein coding. A high stability and tissue- and disease-specific expression allow circRNAs to serve as potential biomarkers both for diseases and prognosis. CircRNAs function in bone remodeling by directly participating in bone-related signaling pathways and by forming the circRNA-miRNA-mRNA axis. Studies have seldom reported on the low incidence of circRNAs in genetic bone disorders. The current study reviews the characteristics of circRNAs and recent research on their role in rare hereditary bone diseases.

Bilateral vision loss due to Leber's hereditary optic neuropathy after long-term alcohol, nicotine and drug abuse.

PubMed

Maass, Johanna; Matthé, Egbert

2018-04-01

Leber's hereditary optic neuropathy is relatively rare, and no clinical pathognomonic signs exist. We present a rare case of bilateral vision loss of a patient with multiple drug abuse in the history. A 31-year-old man presented with a history of progressive, decreased vision in both eyes for 6 month. On examination, his visual acuity was hand motion in both eyes. Funduscopy demonstrated a temporal pallor of the optic disc. Goldmann visual field perimetry showed a crescent visual field in the right eye and a circular decrease to less than 50 ° in the left eye. Electroretinogram showed a scotopic b-wave amplitude reduction. Optical coherence tomographies, Heidelberg Retina tomography, visual evoked potentials, and magnetic resonance imaging with contrast as well as blood tests were normal. The patient reported to consume various kinds of drugs as well as recreational drug use and alcohol consumption since he was 16 years old. We started a hemodilution therapy, believing the patient suffered from a bilateral, toxic optic neuropathy due to his lifestyle. Laboratory results later on showed Leber's hereditary optic neuropathy. Leber's hereditary optic neuropathy is a rare disease without a typical, pathognomonic presentation. Even though the patient gave good reasons for a toxic optic neuropathy, one should never stop to test for other diseases.

Progress towards genetic and pharmacological therapies for keratin genodermatoses: current perspective and future promise

PubMed Central

Chamcheu, Jean Christopher; Wood, Gary S.; Siddiqui, Imtiaz A.; Syed, Deeba N.; Adhami, Vaqar M.; Teng, Joyce M.; Mukhtar, Hasan

2012-01-01

Hereditary keratin disorders of the skin and its appendages comprise a large group of clinically heterogeneous disfiguring blistering and ichthyotic diseases, primarily characterized by the loss of tissue integrity, blistering and hyperkeratosis in severely affected tissues. Pathogenic mutations in keratins cause these afflictions. Typically, these mutations in concert with characteristic features have formed the basis for improved disease diagnosis, prognosis and most recently therapy development. Examples include epidermolysis bullosa simplex, keratinopathic ichthyosis, pachyonychia congenita and several other tissue-specific hereditary keratinopathies. Understanding the molecular and genetic events underlying skin dysfunction has initiated alternative treatment approaches that may provide novel therapeutic opportunities for affected patients. Animal and in vitro disease modelling studies have shed more light on molecular pathogenesis, further defining the role of keratins in disease processes and promoting the translational development of new gene and pharmacological therapeutic strategies. Given that the molecular basis for these monogenic disorders is well established, gene therapy and drug discovery targeting pharmacological compounds with the ability to reinforce the compromised cytoskeleton may lead to promising new therapeutic strategies for treating hereditary keratinopathies. In this review, we will summarize and discuss recent advances in the preclinical and clinical modelling and development of gene, natural product, pharmacological and protein-based therapies for these disorders, highlighting the feasibility of new approaches for translational clinical therapy. PMID:22716242

Genetic heterogeneity of motor neuropathies.

PubMed

Bansagi, Boglarka; Griffin, Helen; Whittaker, Roger G; Antoniadi, Thalia; Evangelista, Teresinha; Miller, James; Greenslade, Mark; Forester, Natalie; Duff, Jennifer; Bradshaw, Anna; Kleinle, Stephanie; Boczonadi, Veronika; Steele, Hannah; Ramesh, Venkateswaran; Franko, Edit; Pyle, Angela; Lochmüller, Hanns; Chinnery, Patrick F; Horvath, Rita

2017-03-28

To study the prevalence, molecular cause, and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the North of England. Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex neurologic disease predominantly affecting the motor nerves (hereditary motor neuropathy plus, 25 patients). The prevalence of dHMN is 2.14 affected individuals per 100,000 inhabitants (95% confidence interval 1.62-2.66) in the North of England. Causative mutations were identified in 26 out of 73 index patients (35.6%). The diagnostic rate in the dHMN subgroup was 32.5%, which is higher than previously reported (20%). We detected a significant defect of neuromuscular transmission in 7 cases and identified potentially causative mutations in 4 patients with multifocal demyelinating motor neuropathy. Many of the genes were shared between dHMN and motor CMT2, indicating identical disease mechanisms; therefore, we suggest changing the classification and including dHMN also as a subcategory of Charcot-Marie-Tooth disease. Abnormal neuromuscular transmission in some genetic forms provides a treatable target to develop therapies. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Progress towards genetic and pharmacological therapies for keratin genodermatoses: current perspective and future promise.

PubMed

Chamcheu, Jean Christopher; Wood, Gary S; Siddiqui, Imtiaz A; Syed, Deeba N; Adhami, Vaqar M; Teng, Joyce M; Mukhtar, Hasan

2012-07-01

Hereditary keratin disorders of the skin and its appendages comprise a large group of clinically heterogeneous disfiguring blistering and ichthyotic diseases, primarily characterized by the loss of tissue integrity, blistering and hyperkeratosis in severely affected tissues. Pathogenic mutations in keratins cause these afflictions. Typically, these mutations in concert with characteristic features have formed the basis for improved disease diagnosis, prognosis and most recently therapy development. Examples include epidermolysis bullosa simplex, keratinopathic ichthyosis, pachyonychia congenita and several other tissue-specific hereditary keratinopathies. Understanding the molecular and genetic events underlying skin dysfunction has initiated alternative treatment approaches that may provide novel therapeutic opportunities for affected patients. Animal and in vitro disease modelling studies have shed more light on molecular pathogenesis, further defining the role of keratins in disease processes and promoting the translational development of new gene and pharmacological therapeutic strategies. Given that the molecular basis for these monogenic disorders is well established, gene therapy and drug discovery targeting pharmacological compounds with the ability to reinforce the compromised cytoskeleton may lead to promising new therapeutic strategies for treating hereditary keratinopathies. In this review, we will summarize and discuss recent advances in the preclinical and clinical modelling and development of gene, natural product, pharmacological and protein-based therapies for these disorders, highlighting the feasibility of new approaches for translational clinical therapy. © 2012 John Wiley & Sons A/S.

Hereditary cancer genes are highly susceptible to splicing mutations

PubMed Central

Soemedi, Rachel; Maguire, Samantha; Murray, Michael F.; Monaghan, Sean F.

2018-01-01

Substitutions that disrupt pre-mRNA splicing are a common cause of genetic disease. On average, 13.4% of all hereditary disease alleles are classified as splicing mutations mapping to the canonical 5′ and 3′ splice sites. However, splicing mutations present in exons and deeper intronic positions are vastly underreported. A recent re-analysis of coding mutations in exon 10 of the Lynch Syndrome gene, MLH1, revealed an extremely high rate (77%) of mutations that lead to defective splicing. This finding is confirmed by extending the sampling to five other exons in the MLH1 gene. Further analysis suggests a more general phenomenon of defective splicing driving Lynch Syndrome. Of the 36 mutations tested, 11 disrupted splicing. Furthermore, analyzing past reports suggest that MLH1 mutations in canonical splice sites also occupy a much higher fraction (36%) of total mutations than expected. When performing a comprehensive analysis of splicing mutations in human disease genes, we found that three main causal genes of Lynch Syndrome, MLH1, MSH2, and PMS2, belonged to a class of 86 disease genes which are enriched for splicing mutations. Other cancer genes were also enriched in the 86 susceptible genes. The enrichment of splicing mutations in hereditary cancers strongly argues for additional priority in interpreting clinical sequencing data in relation to cancer and splicing. PMID:29505604

Identification of a Heterozygous SPG11 Mutation by Clinical Exome Sequencing in a Patient With Hereditary Spastic Paraplegia: A Case Report.

PubMed

Oh, Ja-Young; Do, Hyun Jung; Lee, Seungok; Jang, Ja-Hyun; Cho, Eun-Hae; Jang, Dae-Hyun

2016-12-01

Next-generation sequencing, such as whole-genome sequencing, whole-exome sequencing, and targeted panel sequencing have been applied for diagnosis of many genetic diseases, and are in the process of replacing the traditional methods of genetic analysis. Clinical exome sequencing (CES), which provides not only sequence variation data but also clinical interpretation, aids in reaching a final conclusion with regards to genetic diagnosis. Sequencing of genes with clinical relevance rather than whole exome sequencing might be more suitable for the diagnosis of known hereditary disease with genetic heterogeneity. Here, we present the clinical usefulness of CES for the diagnosis of hereditary spastic paraplegia (HSP). We report a case of patient who was strongly suspected of having HSP based on her clinical manifestations. HSP is one of the diseases with high genetic heterogeneity, the 72 different loci and 59 discovered genes identified so far. Therefore, traditional approach for diagnosis of HSP with genetic analysis is very challenging and time-consuming. CES with TruSight One Sequencing Panel, which enriches about 4,800 genes with clinical relevance, revealed compound heterozygous mutations in SPG11 . One workflow and one procedure can provide the results of genetic analysis, and CES with enrichment of clinically relevant genes is a cost-effective and time-saving diagnostic tool for diseases with genetic heterogeneity, including HSP.

What Is Celiac Disease? How Do I Live with It?

ERIC Educational Resources Information Center

Blaska, Joan

2007-01-01

Celiac disease, also known as celiac sprue, is a hereditary, autoimmune disease that causes a sensitivity to gluten, which is a protein found in wheat, rye, and barley. The key symptoms of celiac disease are diarrhea, constipation, gas, bloating, backaches, stomachaches, nausea, anemia, fatigue, osteoporosis, stunted growth in children, and weight…

Axon Transport and Neuropathy

PubMed Central

Tourtellotte, Warren G.

2017-01-01

Peripheral neuropathies are highly prevalent and are most often associated with chronic disease, side effects from chemotherapy, or toxic-metabolic abnormalities. Neuropathies are less commonly caused by genetic mutations, but studies of the normal function of mutated proteins have identified particular vulnerabilities that often implicate mitochondrial dynamics and axon transport mechanisms. Hereditary sensory and autonomic neuropathies are a group of phenotypically related diseases caused by monogenic mutations that primarily affect sympathetic and sensory neurons. Here, I review evidence to indicate that many genetic neuropathies are caused by abnormalities in axon transport. Moreover, in hereditary sensory and autonomic neuropathies. There may be specific convergence on gene mutations that disrupt nerve growth factor signaling, upon which sympathetic and sensory neurons critically depend. PMID:26724390

Iron Storage Disease: Facts, Fiction and Progress

PubMed Central

Beutler, Ernest

2007-01-01

There are many forms of iron storage disease, some hereditary and some acquired. The most common of the hereditary forms is HFE-associated hemochromatosis, and it is this disorder that is the main focus of this presentation. The body iron content is regulated by controlling absorption, and studies in the past decade have clarified, in part, how this regulation functions. A 25 amino acid peptide hepcidin is upregulated by iron and by inflammation, and it inhibits iron absorption and traps iron in macrophages by binding to and causing degradation of the iron transport protein ferroportin. Most forms of hemochromatosis results from dysregulation of hepcidin or defects of hepcidin or ferroportin themselves. PMID:17540589

Osler-Weber-Rendu syndrome

MedlinePlus

... your provider what other precautions you should take. Support Groups These resources can provide more information on HHT: Centers for Disease Control and Prevention -- www.cdc.gov/ncbddd/hht Cure HHT -- curehht.org National Organization for Rare Disorders -- rarediseases.org/rare-diseases/hereditary- ...

Pathogenic proline mutation in the linker between spectrin repeats: disease caused by spectrin unfolding

PubMed Central

Johnson, Colin P.; Gaetani, Massimiliano; Ortiz, Vanessa; Bhasin, Nishant; Harper, Sandy

2007-01-01

Pathogenic mutations in α and β spectrin result in a variety of syndromes, including hereditary elliptocytosis (HE), hereditary pyropoikilocytosis (HPP), and hereditary spherocytosis (HS). Although some mutations clearly lie at sites of interaction, such as the sites of spectrin α-βtetramer formation, a surprising number of HE-causing mutations have been identified within linker regions between distal spectrin repeats. Here we apply solution structural and single molecule methods to the folding and stability of recombinant proteins consisting of the first 5 spectrin repeats of α-spectrin, comparing normal spectrin with a pathogenic linker mutation, Q471P, between repeats R4 and R5. Results show that the linker mutation destabilizes a significant fraction of the 5-repeat construct at 37°C, whereas the WT remains fully folded well above body temperature. In WT protein, helical linkers propagate stability from one repeat to the next, but the mutation disrupts the stabilizing influence of adjacent repeats. The results suggest a molecular mechanism for the high frequency of disease caused by proline mutations in spectrin linkers. PMID:17192394

Cerebellar ataxia and intrathecal baclofen therapy: Focus on patients´ experiences

PubMed Central

Berntsson, Shala Ghaderi; Landtblom, Anne-Marie; Flensner, Gullvi

2017-01-01

Elucidating patients´ experiences of living with chronic progressive hereditary ataxia and the symptomatic treatment with intrathecal baclofen (ITB) is the objective of the current study. A multicenter qualitative study with four patients included due to the rare combination of hereditary ataxia and ITB therapy was designed to elucidate participants’ experiences through semi-structured interviews. The transcribed text was analyzed according to content analysis guidelines. Overall we identified living in the present/ taking one day at a time as the main theme covering the following categories: 1) Uncertainty about the future as a consequence of living with a hereditary disease; The disease; 2) Impact on life as a whole, 3) Influence on personal life in terms of feeling forced to terminate employment, 4) Limiting daily activities, and 5) ITB therapy, advantages, and disadvantages. Uncertainty about the future was the category that affected participants’ personal life, employment, and daily activities. The participants’ experience of receiving ITB therapy was expressed in terms of improved quality of life due to better body position and movement as well as better sleep and pain relief. PMID:28654671

76 FR 12122 - Disease, Disability, and Injury Prevention and Control Special Emphasis Panel (SEP): The...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-04

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Centers for Disease Control and Prevention Disease, Disability, and Injury Prevention and Control Special Emphasis Panel (SEP): The Association of Genetic Biomarkers and Hereditary Hemochromatosis, DD11-008, Initial Review Correction: This notice was published in...

Spontaneous haemothorax in Osler-Weber-Rendu disease.

PubMed Central

Karnik, A. M.; Sughayer, A.; Fenech, F. F.

1983-01-01

A case of hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu disease) is described who presented with severe, central chest pain mimicking acute myocardial infarction, a presentation which has not been described before. He was found to have developed spontaneous haemothorax which is a very rare complication of this disease. PMID:6622342

Hereditary hemochromatosis of tongue.

PubMed

Al Wayli, Hessa; Rastogi, Sanjay; Verma, Neha

2011-01-01

Hereditary hemochromatosis (HH) refers to several inherited disorders of iron metabolism leading to tissue iron overload. Classical HH is associated with mutations in HFE (C282Y homozygotes or C282Y/H63D compound heterozygotes) and is almost exclusively found in populations of northern European descent. Non-HFE-associated HH is caused by mutations in other recently identified genes involved in iron metabolism. Hepcidin is an iron regulatory hormone that inhibits ferroportin-mediated iron export from enterocytes and macrophages. Defective hepcidin gene expression or function may underlie most forms of HH. Target organs and tissues affected by HH include the liver, heart, pancreas, joints, and skin, with cirrhosis and diabetes mellitus representing late signs of disease in patients with markedly elevated liver iron concentration. Recently, we have encountered the rare representation of this disease of the oral cavity associated with generalized burning sensation of the tongue. The diagnosis was established accidently, from the lab investigations, otherwise the patient was healthy and free from classical signs and symptoms of the disease. The patient was adequately treated by phlebotomy. To conclude, all patients with a chief complaint of burning sensation of the oral cavity and tongue should be adequately screened for hereditary hemochromatosis to prevent the associated mortality and morbidity with the hemochromatosis. Copyright © 2011 Mosby, Inc. All rights reserved.

Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy

PubMed Central

Iommarini, Luisa; Giordano, Luca; Maresca, Alessandra; Pisano, Annalinda; Valentino, Maria Lucia; Caporali, Leonardo; Liguori, Rocco; Deceglie, Stefania; Roberti, Marina; Fanelli, Francesca; Fracasso, Flavio; Ross-Cisneros, Fred N.; D’Adamo, Pio; Hudson, Gavin; Pyle, Angela; Yu-Wai-Man, Patrick; Chinnery, Patrick F.; Zeviani, Massimo; Salomao, Solange R.; Berezovsky, Adriana; Belfort, Rubens; Ventura, Dora Fix; Moraes, Milton; Moraes Filho, Milton; Barboni, Piero; Sadun, Federico; De Negri, Annamaria; Sadun, Alfredo A.; Tancredi, Andrea; Mancini, Massimiliano; d’Amati, Giulia; Loguercio Polosa, Paola; Cantatore, Palmiro

2014-01-01

Leber’s hereditary optic neuropathy is a maternally inherited blinding disease caused as a result of homoplasmic point mutations in complex I subunit genes of mitochondrial DNA. It is characterized by incomplete penetrance, as only some mutation carriers become affected. Thus, the mitochondrial DNA mutation is necessary but not sufficient to cause optic neuropathy. Environmental triggers and genetic modifying factors have been considered to explain its variable penetrance. We measured the mitochondrial DNA copy number and mitochondrial mass indicators in blood cells from affected and carrier individuals, screening three large pedigrees and 39 independently collected smaller families with Leber’s hereditary optic neuropathy, as well as muscle biopsies and cells isolated by laser capturing from post-mortem specimens of retina and optic nerves, the latter being the disease targets. We show that unaffected mutation carriers have a significantly higher mitochondrial DNA copy number and mitochondrial mass compared with their affected relatives and control individuals. Comparative studies of fibroblasts from affected, carriers and controls, under different paradigms of metabolic demand, show that carriers display the highest capacity for activating mitochondrial biogenesis. Therefore we postulate that the increased mitochondrial biogenesis in carriers may overcome some of the pathogenic effect of mitochondrial DNA mutations. Screening of a few selected genetic variants in candidate genes involved in mitochondrial biogenesis failed to reveal any significant association. Our study provides a valuable mechanism to explain variability of penetrance in Leber’s hereditary optic neuropathy and clues for high throughput genetic screening to identify the nuclear modifying gene(s), opening an avenue to develop predictive genetic tests on disease risk and therapeutic strategies. PMID:24369379

The evolution of colorectal cancer genetics—Part 1: from discovery to practice

PubMed Central

Schlussel, Andrew T.; Gagliano, Ronald A.; Eggerding, Faye; Donlon, Timothy; Berenberg, Jeffrey; Lynch, Henry T.

2014-01-01

Colorectal cancer (CRC) is an increasing burden on our society. Identifying those who are at the greatest risk and improving triage for treatment will have the greatest impact on healthcare. CRC is a prime paradigm for cancer genetics: the majority of disease results from stages of progression lending itself to prevention by early detection of the pre-disease (neoplastic) state. Approximately 10% represent well defined hereditary cancer syndromes. Hereditary CRC has the added benefit that many are slow growing and family members are armed with the knowledge of potential risk of associated carcinomas and empowerment to reduce the disease burden. This knowledge provides the indication for early endoscopic and/or surgical intervention for prevention or treatment of an entire family cohort. The molecular basis of CRC allows enhanced characterization of carcinomas, leading to targeted therapies. PMID:25276405

[Hereditary motor and sensory neuropathy type 4A].

PubMed

2010-01-01

The first in the Russian Federation clinical cases of patients with autosomal-recessive type of hereditary motor and sensory neuropathy, type 4A, (HMSN 4A) are presented. In all cases, the diagnosis has been verified using molecular-genetic methods (DNA diagnostics). An analysis of features of clinical manifestations was performed in patients, aged from 5 to 34 years, with different disease duration (from 3-to 29 years). Criteria of selection of patients for DNA diagnostics for searching mutations in the GDAP1 gene are specified.

Overlapping molecular pathological themes link Charcot-Marie-Tooth neuropathies and hereditary spastic paraplegias.

PubMed

Timmerman, Vincent; Clowes, Virginia E; Reid, Evan

2013-08-01

In this review we focus on Charcot-Marie-Tooth (CMT) neuropathies and hereditary spastic paraplegias (HSPs). Although these diseases differ in whether they primarily affect the peripheral or central nervous system, both are genetically determined, progressive, long axonopathies that affect motor and sensory pathways. This commonality suggests that there might be similarities in the molecular pathology underlying these conditions, and here we compare the molecular genetics and cellular pathology of the two groups. Copyright © 2012 Elsevier Inc. All rights reserved.

Genetic testing in hyperlipidemia.

PubMed

Bilen, Ozlem; Pokharel, Yashashwi; Ballantyne, Christie M

2015-05-01

Hereditary dyslipidemias are often underdiagnosed and undertreated, yet with significant health implications, most importantly causing preventable premature cardiovascular diseases. The commonly used clinical criteria to diagnose hereditary lipid disorders are specific but are not very sensitive. Genetic testing may be of value in making accurate diagnosis and improving cascade screening of family members, and potentially, in risk assessment and choice of therapy. This review focuses on using genetic testing in the clinical setting for lipid disorders, particularly familial hypercholesterolemia. Copyright © 2015 Elsevier Inc. All rights reserved.

Genetic Testing in Hyperlipidemia.

PubMed

Bilen, Ozlem; Pokharel, Yashashwi; Ballantyne, Christie M

2016-03-01

Hereditary dyslipidemias are often underdiagnosed and undertreated, yet with significant health implications, most importantly causing preventable premature cardiovascular diseases. The commonly used clinical criteria to diagnose hereditary lipid disorders are specific but are not very sensitive. Genetic testing may be of value in making accurate diagnosis and improving cascade screening of family members, and potentially, in risk assessment and choice of therapy. This review focuses on using genetic testing in the clinical setting for lipid disorders, particularly familial hypercholesterolemia. Copyright © 2016 Elsevier Inc. All rights reserved.

[Peripheral artery disease in patients younger than 50 years old: Which etiology?].

PubMed

Cotard, S; Nouni, A; Jaquinandi, V; Gladu, G; Kaladji, A; Mahé, G

2016-09-01

Peripheral arterial disease (PAD) encompasses disease of all arteries of the body except the coronary arteries. The main etiology whatever the patient's age is atherosclerosis. Different etiologies can induce PAD especially when patients are younger than 50 years old and have no cardiovascular risk factors (smoking, hypertension, diabetes…). PAD that appears before 50 years old can be named juvenile PAD (JPAD) although there is no consensus about the definition. The aim of this work is to present the different etiologies of JPAD according to their hereditary, acquired or mixed origins. The following hereditary causes are addressed: Marfan syndrome, Ehlers-Danlos syndrome, homocystinuria, pseudoxanthoma elasticum, osteogenesis imperfecta "mid-aortic" syndrome. Among the acquired etiologies, inflammatory JPADs without extravascular signs such as atherosclerosis and Buerger's disease, inflammatory JPADs with extravascular signs as Takayasu's disease, Behçet's disease and Cogan's syndrome, JPADs like aortitis, embolic JPADs, iatrogenic JPADs, and mechanical or traumatic JPADs are described. Finally, mixed origins as thrombotic disease and fibromuscular dysplasia are presented. This work will assist clinicians in the diagnosis of JPAD. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Nonalcoholic Fatty Liver Disease

MedlinePlus

... fatty liver, alcoholic steatohepatitis, ascites, choline deficiency, cirrhosis, drug-induced fatty liver, edema, encephalopathy, glycogen storage disorder, gynecomastia, hepatic steatosis, hepatomegaly, hereditary fructose intolerance, homocystinuria, hyperlipidemia, ...

The Application of Next-Generation Sequencing for Mutation Detection in Autosomal-Dominant Hereditary Hearing Impairment.

PubMed

Gürtler, Nicolas; Röthlisberger, Benno; Ludin, Katja; Schlegel, Christoph; Lalwani, Anil K

2017-07-01

Identification of the causative mutation using next-generation sequencing in autosomal-dominant hereditary hearing impairment, as mutation analysis in hereditary hearing impairment by classic genetic methods, is hindered by the high heterogeneity of the disease. Two Swiss families with autosomal-dominant hereditary hearing impairment. Amplified DNA libraries for next-generation sequencing were constructed from extracted genomic DNA, derived from peripheral blood, and enriched by a custom-made sequence capture library. Validated, pooled libraries were sequenced on an Illumina MiSeq instrument, 300 cycles and paired-end sequencing. Technical data analysis was performed with SeqMonk, variant analysis with GeneTalk or VariantStudio. The detection of mutations in genes related to hearing loss by next-generation sequencing was subsequently confirmed using specific polymerase-chain-reaction and Sanger sequencing. Mutation detection in hearing-loss-related genes. The first family harbored the mutation c.5383+5delGTGA in the TECTA-gene. In the second family, a novel mutation c.2614-2625delCATGGCGCCGTG in the WFS1-gene and a second mutation TCOF1-c.1028G>A were identified. Next-generation sequencing successfully identified the causative mutation in families with autosomal-dominant hereditary hearing impairment. The results helped to clarify the pathogenic role of a known mutation and led to the detection of a novel one. NGS represents a feasible approach with great potential future in the diagnostics of hereditary hearing impairment, even in smaller labs.

[Double mutant alleles in the EXT1 gene not previously reported in a teenager with hereditary multiple exostoses].

PubMed

Cammarata-Scalisi, Francisco; Cozar, Mónica; Grinberg, Daniel; Balcells, Susana; Asteggiano, Carla G; Martínez-Domenech, Gustavo; Bracho, Ana; Sánchez, Yanira; Stock, Frances; Delgado-Luengo, Wilmer; Zara-Chirinos, Carmen; Chacín, José Antonio

2015-04-01

Hereditary forms of multiple exostoses, now called EXT1/EXT2-CDG within Congenital Disorders of Glycosylation, are the most common benign bone tumors in humans and clinical description consists of the formation of several cartilage-capped bone tumors, usually benign and localized in the juxta-epiphyseal region of long bones, although wide body dissemination in severe cases is not uncommon. Onset of the disease is variable ranging from 2-3 years up to 13-15 years with an estimated incidence ranging from 1/18,000 to 1/50,000 cases in European countries. We present a double mutant alleles in the EXT1 gene not previously reported in a teenager and her family with hereditary multiple exostoses.

Increased duodenal DMT-1 expression and unchanged HFE mRNA levels in HFE-associated hereditary hemochromatosis and iron deficiency.

PubMed

Byrnes, V; Barrett, S; Ryan, E; Kelleher, T; O'Keane, C; Coughlan, B; Crowe, J

2002-01-01

HFE-associated hereditary hemochromatosis is characterized by imbalances of iron homeostasis and alterations in intestinal iron absorption. The identification of the HFE gene and the apical iron transporter divalent metal transporter-1, DMT-1, provide a direct method to address the mechanisms of iron overload in this disease. The aim of this study was to evaluate the regulation of duodenal HFE and DMT-1 gene expression in HFE-associated hereditary hemochromatosis. Small bowel biopsies and serum iron indices were obtained from a total of 33 patients. The study population comprised 13 patients with hereditary hemochromatosis (C282Y homozygous), 10 patients with iron deficiency anemia, and 10 apparently healthy controls, all of whom were genotyped for the two common mutations in the HFE gene (C282Y and H63D). Total RNA was isolated from tissue and amplified via RT-PCR for HFE, DMT-1, and the internal control GAPDH. DMT-1 protein expression was additionally assessed by immunohistochemistry. Levels of HFE mRNA did not differ significantly between patient groups (P = 0.09), specifically between C282Y homozygotes and iron deficiency anemic patients, when compared to controls (P = 0.09, P = 0.9, respectively). In contrast, DMT-1 mRNA levels were at least twofold greater in patients with hereditary hemochromatosis and iron deficiency anemia when compared to controls (P = 0.02, P = 0.01, respectively). Heightened DMT-1 protein expression correlated with mRNA levels in all patients. Loss of HFE function in hereditary hemochromatosis is not derived from inhibition of its gene expression. DMT-1 expression in C282Y homozygote subjects is consistent with the hypothesis of a "paradoxical" duodenal iron deficiency in hereditary hemochromatosis. The observed twofold upregulation of the DMT-1 is consistent with the slow but steady increase in body iron stores observed in those presenting with clinical features of hereditary hemochromatosis.

Thoracic aortic dissection in a patient with autosomal dominant polycystic kidney disease.

PubMed

Adeola, T; Adeleye, O; Potts, J L; Faulkner, M; Oso, A

2001-01-01

Autosomal dominant polycystic kidney disease is one of the most common hereditary diseases, and frequently has well defined extrarenal manifestations. Very few cases of aortic aneurysms associated with this disorder are described in literature. We report a 42-year-old male with autosomal dominant polycystic kidney disease presenting with dissecting aneurysm of the thoracic aorta.

Inherited Retinal Degenerative Disease Registry

ClinicalTrials.gov

2017-09-13

Eye Diseases Hereditary; Retinal Disease; Achromatopsia; Bardet-Biedl Syndrome; Bassen-Kornzweig Syndrome; Batten Disease; Best Disease; Choroidal Dystrophy; Choroideremia; Cone Dystrophy; Cone-Rod Dystrophy; Congenital Stationary Night Blindness; Enhanced S-Cone Syndrome; Fundus Albipunctatus; Goldmann-Favre Syndrome; Gyrate Atrophy; Juvenile Macular Degeneration; Kearns-Sayre Syndrome; Leber Congenital Amaurosis; Refsum Syndrome; Retinitis Pigmentosa; Retinitis Punctata Albescens; Retinoschisis; Rod-Cone Dystrophy; Rod Dystrophy; Rod Monochromacy; Stargardt Disease; Usher Syndrome

Congenital and inherited neurologic diseases in dogs and cats: Legislation and its effect on purchase in Italy

PubMed Central

Passantino, Annamaria; Masucci, Marisa

2016-01-01

Many of the congenital neurologic diseases can result in incapacity or death of the animal. Some of them, such as idiopathic epilepsy and hydrocephalus, exhibit breed or familial predisposition and a genetic basis was proved or suggested. Some diseases can be presumptively diagnosed after a detailed signalment (breed predisposition), history (e.g. family history because many of these defects have familial tendencies), and through physical exam; other diagnostic methods (radiography, computed tomography, magnetic resonance, electrophysiologic tests, etc.) can provide supportive evidence for the congenital defect and help to confirm the diagnosis. Some cases can lead to civil law-suits when the lesions are congenital, but not easily recognizable, or when the lesions are hereditary but tend to became manifest only after some time (more than 12 months after the date of purchase, e.g., after the vice-free guarantee period has expired). Moreover, quite frequently an early diagnosis is not made because there are delays in consulting the veterinarian or the general practitioner veterinarian does not perceive subtle signs. This study was designed to focus on the medico-legal aspects concerning the buying and selling in Italy of dogs and cats affected by congenital and hereditary neurologic diseases that could constitute vice in these animals. While adequate provisions to regulate in detail the various aspects of pet sale have still to be drawn up by legislators, it may be helpful to involve breeders, by obliging them by contract to extend guarantees in the case of hereditary lesions, including neurologic diseases. PMID:27284217

Health check-ups and family screening allow detection of hereditary hemochromatosis with less advanced liver fibrosis and survival comparable with the general population.

PubMed

Aleman, Soo; Endalib, Sanam; Stål, Per; Lööf, Lars; Lindgren, Stefan; Sandberg-Gertzén, Hanna; Almer, Sven; Olsson, Sigvard; Danielsson, Ake; Wallerstedt, Sven; Hultcrantz, Rolf

2011-09-01

The information concerning the morbidity and mortality of hereditary hemochromatosis is based primarily on clinical cohorts of symptomatic patients. The major aim of this study was to analyze the long-term prognosis for Swedish patients with this condition, with respect to both clinical features and survival, in relation to the route by which the disease was detected. 373 patients with hemochromatosis detected through routine health check-ups (n = 153), family screening (n = 44), symptoms of arthralgia (n = 23), investigation of other diseases/symptoms (n = 108) or signs of liver disease (n = 45) were monitored for a mean period of 11.9 ± 5.8 years. The degree of liver fibrosis and survival were analyzed. Overall survival among these patients was not significantly different from that of a matched normal population. The patients diagnosed through health check-ups and family screening were detected at an earlier age and had the highest rate of survival. Liver biopsy at the time of diagnosis revealed cirrhosis in 9% of those detected through the health check-ups and 5% in the case of family screening, compared with 13% for the group with arthralgia, 17% for other diseases/symptoms and 42% for liver disease. Health check-ups and family screening allow detection of hereditary hemochromatosis at an earlier age and with less advanced liver fibrosis, although a few of these patients have already developed cirrhosis. Our study indicates that iron indices should be included in health check-ups, and if abnormal, should lead to further investigation.