2 Neuroscience2.13 Neurodegeneration
2.13.6 Prion diseases
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Written by Resident Doctor Committee · Published
The prion protein
Prion diseases are caused by misfolding of the prion protein (PrP), unlike neurodegenerations defined by alpha-synuclein, tau, TDP-43 or huntingtin.
The gene PRNP on chromosome 20 encodes normal cellular prion protein, PrPC, which sits on cell membranes.
Misfolding changes the shape of the protein, not its sequence, and the misfolded protein templates further misfolding without any nucleic acid.
Property | PrPC (normal) | PrPSc (disease) |
|---|---|---|
Structure | Mainly alpha-helical | Rich in beta-sheet |
Protease digestion | Sensitive | Resistant |
Behaviour | Relatively soluble | Aggregates and propagates itself |
Neuropathology
Spongiform change is vacuolation of the grey matter neuropil, which may merge into microcysts, and appears mainly once survival passes 6 to 12 months.
It comes with neuronal loss and reactive gliosis but no inflammatory infiltrate.
Kuru plaques are deposits of prion protein amyloid; variant Creutzfeldt-Jakob disease (CJD) has florid plaques.
The cerebellum is a preferential target, so cerebellar atrophy accompanies cortical atrophy in CJD and ataxia is often early.
The thalamus is targeted in fatal familial insomnia and variant CJD.
Sporadic, inherited and acquired forms
Category | Cause | Examples | Share |
|---|---|---|---|
Sporadic | No known cause | Sporadic CJD | About 85% |
Inherited | Pathogenic PRNP variant | Genetic CJD, Gerstmann-Straussler-Scheinker disease, fatal familial insomnia | About 10 to 15% |
Acquired | Exposure to prions | Variant CJD, iatrogenic CJD, kuru | Small minority |
Syndrome | Features |
|---|---|
Gerstmann-Straussler-Scheinker disease | Often cerebellar onset, slow progression over years |
Fatal familial insomnia | Usually D178N with methionine at codon 129; thalamic disease with disordered sleep and autonomic and motor changes |
Kuru | Spread among the Fore by eating infected brain; cerebellar syndrome; incubation can last decades |
Kuru is a transmissible spongiform encephalopathy, not a culture-bound psychiatric syndrome.
Sporadic and variant CJD compared
Feature | Sporadic CJD | Variant CJD |
|---|---|---|
Onset age | Mostly 55 to 75 | Mostly in the twenties |
Early features | Rapid cognitive decline, ataxia, startle-sensitive myoclonus | Psychiatric and painful sensory symptoms |
Course | Months | Often over a year |
Electroencephalogram (EEG) | Periodic sharp-wave complexes | Usually lacks them |
Magnetic resonance imaging (MRI) | High signal in caudate, putamen and cortex | Pulvinar sign |
Prion protein outside the brain | None | Accumulates in lymphoid tissue |
Investigations
EEG in sporadic CJD shows generalised periodic sharp-wave complexes at about one per second in around two-thirds of cases, emerging after early non-specific slowing.
The pulvinar sign is bilateral symmetrical high signal in the posterior thalamus on FLAIR (fluid-attenuated inversion recovery), T2 or diffusion MRI, brighter than the striatum.
Cerebrospinal fluid (CSF) 14-3-3 protein marks rapid neuronal destruction and supports sporadic CJD, but it also rises after stroke and in viral encephalitis.
RT-QuIC (real-time quaking-induced conversion) on CSF amplifies the seeding activity of abnormal prion protein itself, so it is highly specific.
A positive tonsillar biopsy supports variant CJD; it does not help in sporadic CJD, where prion protein stays in the nervous system.