Prion Diseases

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.

Rapidly Progressive Dementia

“…Perhaps the prototypical RPDs are prion diseases, such as Jakob-Creutzfeldt disease, which was covered in detail in the article “Prion Diseases” by Michael D. Geschwind, MD, PhD, 2 in the December 2015 Continuum issue and thus is not discussed in detail in this article. (As discussed in the December 2015 article, Jakob-Creutzfeldt disease was commonly referred to for many decades as Jakob or Jakob-Creutzfeldt disease until Clarence J. Gibbs, a prominent researcher in the field, started using the term Creutzfeldt-Jakob.…”

“…CSF pleocytosis or elevated CSF IgG index or oligoclonal bands might indicate an autoimmune or inflammatory process, such as paraneoplastic or other neuroimmunologic conditions. Although oligoclonal bands or elevated IgG index can occur in Jakob-Creutzfeldt disease, 2 their presence probably should prompt an autoimmune and paraneoplastic evaluation. In the author’s UCSF Jakob-Creutzfeldt disease–RPD cohort, several patients with RPD were identified who had either an elevated IgG index or oligoclonal bands and the presence of novel antineuronal antibodies in their serum and/or CSF.…”

“…Although some patients had cancer, in many, no cancers were identified despite thorough evaluation. 5,16,17 At the author’s center, sending the CSF biomarkers 14-3-3, total tau (t-tau), and neuron-specific enolase is always recommended, not necessarily as diagnostic tests for prion disease, because they are not, 2 but rather as markers of rapid neuronal injury. If these biomarkers are elevated, they help confirm the history of a rapidly progressive neurologic condition.…”

“…If prion disease is in the differential, the CSF real-time quaking induced conversion (RT-QuIC) test that detects prion seeding activity should be performed. 2 If AD is a consideration, consider sending CSF for phosphorylated tau (p-tau) and amyloid-β 42 (Aβ 42 ). As Aβ 42 sticks very strongly to regular plastic (lowering the measured value of the enzyme-linked immunosorbent assay [ELISA]), only polypropylene tubes should be used for collection; the CSF for that test should not touch regular plastic tubes or the manometer found in lumbar puncture trays.…”

“…41 Several other infections to consider are shown in Table 7-4 and in the December 2015 issue of Continuum . 2 …”