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Review
. 2015 Dec;21(6 Neuroinfectious Disease):1612-38.
doi: 10.1212/CON.0000000000000251.

Prion Diseases

Michael D Geschwind
Review

Prion Diseases

Michael D Geschwind. Continuum (Minneap Minn). 2015 Dec.

Abstract

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.

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Figures

FIGURE 4-1
FIGURE 4-1
Pathologic features of prion disease. A, Hematoxylin and eosin (H&E) staining demonstrates typical spongiform degeneration (vacuolation) of the gray matter neuropil characteristic of Jakob-Creutzfeldt disease. This feature is less obvious in fatal familial insomnia and Gerstmann-Sträussler-Scheinker syndrome. B, Prion protein (PrP)-positive multicentric plaques are pathognomonic for Gerstmann-Sträussler-Scheinker syndrome. These are mostly present within the molecular layer of the cerebellum but may be diffusely present throughout the cerebrum. C, Glial fibrillary astrocytic protein (GFAP) antibodies demonstrate hypertrophy and proliferation of astrocytes. This feature is present in all prion subtypes. In fatal familial insomnia, this is often found focally within the anterior nucleus and dorsomedial nucleus of the thalamus and brainstem in combination with neuronal dropout. In Gerstmann-Sträussler-Scheinker syndrome it may parallel PrP plaque pathology. D, The florid plaques of variant Jakob-Creutzfeldt disease consist of dense core PrP amyloid deposits surrounded by vacuoles. Reprinted with permission from Brown K, Mastrianni JA, J Ger Psych Neurology. jgp.sagepub.com/content/23/4/277.short. © 2010 SAGE Publications.
FIGURE 4-2
FIGURE 4-2
Western blot comparing the major isoforms observed in the four principal subtypes of prion disease. To the left of the blot displays the prion protein (PrP) segment that is represented in the adjacent blot. The highest molecular weight of PrP is the diglycosylated fraction of PrP, whereas the monoglycosylated and unglycosylated fractions run faster in the gel because of their lower molecular weight. In Jakob-Creutzfeldt disease, fatal familial insomnia, and variant Jakob-Creutzfeldt disease, proteinase-K cleaves approximately the first 67 amino acids of protease-resistant scrapie-related isoform (PrPSc), leaving the PK-resistant core, PrP90-231. In the Jakob-Creutzfeldt disease case shown, the unglycosylated (lowest) band migrates at 21 KDa, indicating Type 1 prions, whereas the fatal familial insomnia case migrates lower, at 19 KDa, indicating Type 2 prions. In most cases of Gerstmann-Sträussler-Scheinker syndrome, a second C-terminal cleavage that removes the glycosylated segment occurs endogenously, leaving a unglycosylated central segment, which usually runs at 7 to 8 KDa. FFI = fatal familial insomnia; GSS = Gerstmann-Sträussler-Scheinker syndrome; JCD = Jakob-Creutzfeldt disease; vJCD = variant Jakob-Creutzfeldt disease. Reprinted with permission from Brown K, Mastrianni JA, J Ger Psych Neurology. jgp.sagepub.com/content/23/4/277.short. © 2010 SAGE Publications.
FIGURE 4-3
FIGURE 4-3
Imaging of the patient in Case 4-1. A, Axial diffusion-weighted imaging (DWI) and B, axial apparent diffusion coefficient (ADC) map 3 months after onset of sporadic Jakob-Creutzfeldt disease. Bilateral restricted diffusion cortical ribboning is shown in the bilateral temporal (solid arrows), parietal (solid arrows), posterior cingulate (dotted arrows) cortices, and the left frontal cortex (dashed arrows).
FIGURE 4-4
FIGURE 4-4
Prion protein (PrP) mutations and polymorphisms. A schematic representation of full-length human PrP is shown with the cleaved signal sequences shown in gray and the octapeptide repeat region in purple. Disease-associated mutations are shown in red and nonsynonymous nonpathogenic genetic variants (polymorphisms) in green. OPRD = octapeptide repeat deletion; OPRI = octapeptide repeat insertion. Reprinted from Lloyd SE, et al, Curr Opin Genet Dev. www.sciencedirect.com/science/article/pii/S0959437X13000300. © 2013 Elsevier Ltd.
FIGURE 4-5
FIGURE 4-5
EEG in a sporadic Jakob-Creutzfeldt disease case. Recordings obtained using a standard international 10- to 20-electrode placement with a singleelectrocardiogram chest electrode (bottom). The EEG shows classic 1 Hz to 2 Hz generalized triphasic periodic sharp-wave complexes as well as diffuse background slowing with poor organization (not shown), suggestive of Jakob-Creutzfeldt disease.
FIGURE 4-6
FIGURE 4-6
Axial brain MRI sequences in a patient with sporadic Jakob-Creutzfeldt disease. Note that the axial fluid-attenuated inversion recovery (FLAIR) sequences (A–D) are generally much less sensitive than the diffusion sequences, particularly diffusion-weighted imaging (DWI) (E–H) and the apparent diffusion coefficient (ADC) map (I–L). The DWI and ADC map show cortical ribboning (solid arrows) in the bilateral parietal, right greater than left frontal and lingula (dashed arrows), and posterior cingulate (arrowheads). Asymmetric involvement of the striatum is also shown (right greater than left) (dotted arrows). Bright regions on DWI are dark on the ADC map, indicating true restricted diffusion of water molecules. This case would meet University of California, San Francisco MRI criteria for sporadic Jakob-Creutzfeldt disease.
FIGURE 4-7
FIGURE 4-7
Imaging of the patient in Case 4-2. Fluid-attenuated inversion recovery (FLAIR) (A), diffusion-weighted imaging (DWI) (B), and apparent diffusion coefficient (ADC) map (C) axial MRI of the patient with a PRNP E200K mutation. Restricted diffusion is seen in the striatum (solid arrows) and several cortical regions (dotted arrows), including left anterior, medial, and posterior cingulate and frontal, insular, and right temporal-parietal cortices. Patients with this mutation typically have prominent striatal restricted diffusion, often with patchy areas of cortical ribboning.
FIGURE 4-8
FIGURE 4-8
Number of reported UK bovine spongiform encephalopathy cases (by year of restriction) 1988–2015 and UK variant Jakob-Creutzfeldt disease onsets 1994–2015 showing relationship between UK bovine spongiform encephalopathy and variant Jakob-Creutzfeldt disease cases by year of onset. Note that a temporal relationship exists between the two curves; as the bovine spongiform encephalopathy cases declined, so have the variant Jakob-Creutzfeldt disease cases. Courtesy of the National CJD Research and Surveillance Unit, Edinburgh, UK.
FIGURE 4-9
FIGURE 4-9
Variant Jakob-Creutzfeldt disease cases by year and by country 1994–2015. Box blot showing variant Jakob-Creutzfeldt disease case onset by country. Most cases have been in the United Kingdom and France. In the Western Hemisphere, there have been two cases in Canada and four in the United States. No new-onset cases have been identified after 2012. Courtesy of the National CJD Research and Surveillance Unit, Edinburgh, UK.
FIGURE 4-10
FIGURE 4-10
Map of the distribution of chronic wasting disease in North America. Reprinted from US Geological Survey. www.nwhc.usgs.gov/disease_information/chronic_wasting_disease/.
See this image and copyright information in PMC

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