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Annual Review of Pathology Jan 2019Prion diseases are rapidly progressive, incurable neurodegenerative disorders caused by misfolded, aggregated proteins known as prions, which are uniquely infectious.... (Review)
Review
Prion diseases are rapidly progressive, incurable neurodegenerative disorders caused by misfolded, aggregated proteins known as prions, which are uniquely infectious. Remarkably, these infectious proteins have been responsible for widespread disease epidemics, including kuru in humans, bovine spongiform encephalopathy in cattle, and chronic wasting disease in cervids, the latter of which has spread across North America and recently appeared in Norway and Finland. The hallmark histopathological features include widespread spongiform encephalopathy, neuronal loss, gliosis, and deposits of variably sized aggregated prion protein, ranging from small, soluble oligomers to long, thin, unbranched fibrils, depending on the disease. Here, we explore recent advances in prion disease research, from the function of the cellular prion protein to the dysfunction triggering neurotoxicity, as well as mechanisms underlying prion spread between cells. We also highlight key findings that have revealed new therapeutic targets and consider unanswered questions for future research.
Topics: Amyloid; Animals; Cattle; Deer; Humans; Neurodegenerative Diseases; Prion Diseases; Prion Proteins
PubMed: 30355150
DOI: 10.1146/annurev-pathmechdis-012418-013109 -
Seminars in Neurology Aug 2019Prion diseases are a phenotypically diverse set of disorders characterized by protease-resistant abnormally shaped proteins known as prions. There are three main groups... (Review)
Review
Prion diseases are a phenotypically diverse set of disorders characterized by protease-resistant abnormally shaped proteins known as prions. There are three main groups of prion diseases, termed sporadic (Creutzfeldt-Jakob disease [CJD], sporadic fatal insomnia, and variably protease-sensitive prionopathy), genetic (genetic CJD, fatal familial insomnia, and Gerstmann-Straussler-Scheinker syndrome), and acquired (kuru, variant CJD, and iatrogenic CJD). This article will review the pathophysiology, genetics, clinical presentations, and diagnostic challenges in patients with prion disease. Case discussions, images, and tables will be used to highlight important characteristics of prion disease and prion mimics.
Topics: Aged; Animals; Creutzfeldt-Jakob Syndrome; Diagnosis, Differential; Humans; Male; Middle Aged; Prion Diseases; Wernicke Encephalopathy
PubMed: 31533183
DOI: 10.1055/s-0039-1687841 -
Continuum (Minneapolis, Minn.) Dec 2015This article presents an update on the clinical aspects of human prion disease, including the wide spectrum of their presentations. (Review)
Review
PURPOSE OF REVIEW
This article presents an update on the clinical aspects of human prion disease, including the wide spectrum of their presentations.
RECENT FINDINGS
Prion diseases, a group of disorders caused by abnormally shaped proteins called prions, occur in sporadic (Jakob-Creutzfeldt disease), genetic (genetic Jakob-Creutzfeldt disease, Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia), and acquired (kuru, variant Jakob-Creutzfeldt disease, and iatrogenic Jakob-Creutzfeldt disease) forms. This article presents updated information on the clinical features and diagnostic methods for human prion diseases. New antemortem potential diagnostic tests based on amplifying prions in order to detect them are showing very high specificity. Understanding of the diversity of possible presentations of human prion diseases continues to evolve, with some genetic forms progressing slowly over decades, beginning with dysautonomia and neuropathy and progressing to a frontal-executive dementia with pathology of combined prionopathy and tauopathy. Unfortunately, to date, all human prion disease clinical trials have failed to show survival benefit. A very rare polymorphism in the prion protein gene recently has been identified that appears to protect against prion disease; this finding, in addition to providing greater understanding of the prionlike mechanisms of neurodegenerative disorders, might lead to potential treatments.
SUMMARY
Sporadic Jakob-Creutzfeldt disease is the most common form of human prion disease. Genetic prion diseases, resulting from mutations in the prion-related protein gene (PRNP), are classified based on the mutation, clinical phenotype, and neuropathologic features and can be difficult to diagnose because of their varied presentations. Perhaps most relevant to this Continuum issue on neuroinfectious diseases, acquired prion diseases are caused by accidental transmission to humans, but fortunately, they are the least common form and are becoming rarer as awareness of transmission risk has led to implementation of measures to prevent such occurrences.
Topics: Humans; Prion Diseases
PubMed: 26633779
DOI: 10.1212/CON.0000000000000251 -
Nature Reviews. Disease Primers Feb 2024Prion diseases share common clinical and pathological characteristics such as spongiform neuronal degeneration and deposition of an abnormal form of a host-derived... (Review)
Review
Prion diseases share common clinical and pathological characteristics such as spongiform neuronal degeneration and deposition of an abnormal form of a host-derived protein, termed prion protein. The characteristic features of prion diseases are long incubation times, short clinical courses, extreme resistance of the transmissible agent to degradation and lack of nucleic acid involvement. Sporadic and genetic forms of prion diseases occur worldwide, of which genetic forms are associated with mutations in PRNP. Human to human transmission of these diseases has occurred due to iatrogenic exposure, and zoonotic forms of prion diseases are linked to bovine disease. Significant progress has been made in the diagnosis of these disorders. Clinical tools for diagnosis comprise brain imaging and cerebrospinal fluid tests. Aggregation assays for detection of the abnormally folded prion protein have a clear potential to diagnose the disease in peripherally accessible biofluids. After decades of therapeutic nihilism, new treatment strategies and clinical trials are on the horizon. Although prion diseases are relatively rare disorders, understanding their pathogenesis and mechanisms of prion protein misfolding has significantly enhanced the field in research of neurodegenerative diseases.
Topics: Animals; Cattle; Humans; Creutzfeldt-Jakob Syndrome; Prion Proteins; Prion Diseases; Brain
PubMed: 38424082
DOI: 10.1038/s41572-024-00497-y -
Continuum (Minneapolis, Minn.) Apr 2016This article presents a practical and informative approach to the evaluation of a patient with a rapidly progressive dementia (RPD). (Review)
Review
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.
Topics: Aged; Dementia; Disease Progression; Female; Humans; Male; Middle Aged; Neuroimaging; Prion Diseases
PubMed: 27042906
DOI: 10.1212/CON.0000000000000319 -
Medicina Clinica Jun 2023Prion diseases are a group of neurodegenerative diseases. The disease-causing agent is a protein (PrP), that is normally produced in the nervous system, aggregated in an... (Review)
Review
Prion diseases are a group of neurodegenerative diseases. The disease-causing agent is a protein (PrP), that is normally produced in the nervous system, aggregated in an abnormal form. The abnormal protein, known as prion (PrP), is capable of self-propagation promoting the misfolding of the normal protein (PrP). These conditions can be acquired sporadically, genetically, or infectiously either by eating meat contaminated with prions or from iatrogenic exposure. The diagnosis of these diseases is often challenging. The use of highly sensitive and specific diagnostic tools, such as MRI and RT-QuIC, may aid in the diagnosis. Neuropathological examination of brain tissue ensures a definite diagnosis. At present, no treatment significantly improves the course of prion diseases; however, an early diagnosis is of paramount importance for patient care decision planning, infection control purposes, and genetic counseling.
Topics: Humans; Creutzfeldt-Jakob Syndrome; Prion Diseases; Prions; Brain
PubMed: 37088611
DOI: 10.1016/j.medcli.2023.03.001 -
Viruses Mar 2019Kuru, the first human prion disease was transmitted to chimpanzees by D. Carleton Gajdusek (1923⁻2008). In this review, we summarize the history of this seminal... (Review)
Review
Kuru, the first human prion disease was transmitted to chimpanzees by D. Carleton Gajdusek (1923⁻2008). In this review, we summarize the history of this seminal discovery, its anthropological background, epidemiology, clinical picture, neuropathology, and molecular genetics. We provide descriptions of electron microscopy and confocal microscopy of kuru amyloid plaques retrieved from a paraffin-embedded block of an old kuru case, named Kupenota. The discovery of kuru opened new vistas of human medicine and was pivotal in the subsequent transmission of Creutzfeldt⁻Jakob disease, as well as the relevance that bovine spongiform encephalopathy had for transmission to humans. The transmission of kuru was one of the greatest contributions to biomedical sciences of the 20th century.
Topics: Animals; Cannibalism; History, 20th Century; Humans; Kuru; Pan troglodytes; Papua New Guinea; Prions
PubMed: 30866511
DOI: 10.3390/v11030232 -
Handbook of Clinical Neurology 2018Genetic prion diseases (gPrDs) are caused by autosomal-dominant mutations in the prion protein gene (PRNP). Although the first PRNP mutations identified, and most since,... (Review)
Review
Genetic prion diseases (gPrDs) are caused by autosomal-dominant mutations in the prion protein gene (PRNP). Although the first PRNP mutations identified, and most since, are PRNP missense, octapeptide repeat insertions, deletion and nonsense mutations have now also been shown to cause gPrD. Based on clinicopathologic features of familial disease, gPrDs historically have been classified into three forms: familial Jakob-Creutzfeldt disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. This classification, however, occurred prior to the identification of PRNP, and although these forms are still recognized, classification now is somewhat more complex. Clinical manifestations, and even pathology, are known to be more heterogeneous and varied than the historic three phenotypic classifications. Most gPrDs either present rapidly with progression of dementia, ataxia, myoclonus, and other motor features leading to death in few months or present more slowly, declining over a few years with mild cognitive impairment, ataxia, or parkinsonism and later dementia; a few very rare mutations, however, present over years to decades with neuropsychiatric disorders and systemic symptoms (gastrointestinal disorders and neuropathy). In this chapter, we review the broad phenotypic spectrum of PRNP mutations causing gPrDs.
Topics: Genetic Predisposition to Disease; Genetic Testing; Humans; Mutation; Prion Diseases; Prion Proteins
PubMed: 29478593
DOI: 10.1016/B978-0-444-64076-5.00029-6 -
Handbook of Clinical Neurology 2018This is the first volume of the Handbook of Clinical Neurology totally devoted to prion diseases. The reason for this choice is to inform neurologists and...
This is the first volume of the Handbook of Clinical Neurology totally devoted to prion diseases. The reason for this choice is to inform neurologists and neuroscientists about the remarkable advances that this field has made in the diagnosis of human and animal prion diseases, understanding the pathogenesis of disease, and in the development of novel in vivo and in vitro models. In recent years, the knowledge of prion replication and mechanisms of prion spreading within the brain and peripheral organs of infected people has also become important for understanding other protein misfolded diseases of the brain, such as Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis. Researchers in these diseases have recognized that the process within an individual leading to the deposition of misfolded proteins within the central nervous system shares remarkable common mechanisms with prion diseases, leading to the terminology of "prion-like diseases."
Topics: Animals; Humans; Prion Diseases; Prions; Protein Folding
PubMed: 29887155
DOI: 10.1016/B978-0-444-63945-5.00028-3 -
Handbook of Clinical Neurology 2018Currently all prion diseases are without effective treatment and are universally fatal. It is increasingly being recognized that the pathogenesis of many...
Currently all prion diseases are without effective treatment and are universally fatal. It is increasingly being recognized that the pathogenesis of many neurodegenerative diseases, such as Alzheimer disease (AD), includes "prion-like" properties. Hence, any effective therapeutic intervention for prion disease could have significant implications for other neurodegenerative diseases. Conversely, therapies that are effective in AD might also be therapeutically beneficial for prion disease. AD-like prion disease has no effective therapy. However, various vaccine and immunomodulatory approaches have shown great success in animal models of AD, with numerous ongoing clinical trials of these potential immunotherapies. More limited evidence suggests that immunotherapies may be effective in prion models and in naturally occurring prion disease. In particular, experimental data suggest that mucosal vaccination against prions can be effective for protection against orally acquired prion infection. Many prion diseases, including natural sheep scrapie, bovine spongiform encephalopathy, chronic wasting disease, and variant Creutzfeldt-Jakob disease, are thought to be acquired peripherally, mainly by oral exposure. Mucosal vaccination would be most applicable to this form of transmission. In this chapter we review various immunologically based strategies which are under development for prion infection.
Topics: Animals; Humans; Immunomodulation; Prion Diseases; Vaccination
PubMed: 29887149
DOI: 10.1016/B978-0-444-63945-5.00023-4