The Generative Brain

What are prion diseases?: research

Plain explanationMore detail

Prion diseases are fatal transmissible neurodegenerative diseases of humans and animals caused by misfolded prion protein. Sporadic CJD accounts for about 85 percent of human cases at a stable incidence of 1 to 2 per million per year, genetic forms for roughly 10 to 15 percent, and acquired forms are now rare, with iatrogenic CJD under 1 percent.

How prion disease develops in the brain
  1. Normal proteinEveryone makes prion protein. It sits on the surface of cells.
  2. A wrong foldSome of the protein folds into the wrong shape.
  3. It spreads its shapeThe misfolded form causes more protein to misfold.
  4. Build-upMisfolded protein gathers and is hard to clear.
  5. Nerve cells are damagedThis causes the symptoms of the illness.

The class is defined by a mechanism rather than by a syndrome. Manka and colleagues (Cell and Tissue Research 2023) group under it Creutzfeldt-Jakob disease, variant CJD, kuru, fatal familial insomnia and Gerstmann-Straussler-Scheinker syndrome in humans, and bovine spongiform encephalopathy in cattle, scrapie in sheep and goats and chronic wasting disease in cervids. What they share is propagation of misfolded host prion protein, described on protein misfolding.

What are the proportions, and how stable are they?

Bellini and colleagues (Viruses 2026) give a stable global incidence of 1 to 2 cases per million per year for sporadic CJD, which accounts for about 85 percent of human cases. They describe genetic forms as less common without giving a percentage, acquired forms as exceedingly rare, and iatrogenic CJD as under 1 percent of all human prion diseases. Appleby and colleagues (Frontiers in Neurology 2022) put genetic prion disease at 10 to 15 percent of all cases.

Those global figures do not transfer to every country. Japanese national surveillance over ten years (Nozaki and colleagues, Brain 2010) classified 1,222 patients as having prion disease: 922 sporadic CJD at 75.5 percent, 216 genetic at 17.7 percent, 81 acquired at 6.6 percent, and 3 unclassified. Eighty of the 81 acquired cases were dura mater graft-associated CJD and one was variant CJD. Both the elevated genetic share and the dura mater cluster are specific to that country and period. Within the Japanese genetic group, V180I at 41.2 percent was the commonest variant, a distribution not seen in European series. Any statement about the proportions of prion disease therefore needs its country and its years attached.

How are sporadic cases subdivided?

By the codon 129 genotype of PRNP combined with the electrophoretic type of protease-resistant PrPSc, type 1 or type 2. Bellini and colleagues list MM1 and MV1, VV2 and MV2, MM2C, MM2T including fatal familial insomnia, and VV1 as the main clinical correlates. MM1 is the commonest subtype, VV2 accounts for about 15 percent of sporadic CJD, MV1 is intermediate in frequency and VV1 is very rare. The molecular type of PrPSc and the codon 129 genotype together shape the histopathological pattern.

Codon 129 also modulates risk and presentation across the class. Nearly all variant CJD patients have been methionine homozygotes, and heterozygotes may show atypical or delayed disease. Detail is on codon 129.

On what basis is a case classified in life?

Bellini and colleagues set out the current tiers for sporadic CJD. A definite diagnosis requires neuropathological or biochemical confirmation of pathological prion protein. Probable requires either rapidly progressive cognitive impairment with at least two supporting clinical features plus a supporting test, meaning a typical EEG, MRI or CSF 14-3-3, or a progressive neuropsychiatric syndrome with positive RT-QuIC in CSF or tissue, with alternative diagnoses excluded. Possible requires rapidly progressive cognitive impairment with at least two clinical features and a duration under 2 years.

They report second-generation RT-QuIC assays at about 99 percent specificity and above 90 percent sensitivity. That headline figure comes from sporadic disease and does not carry over to the genetic forms. In the 302-case, 11-centre genetic cohort of Schmitz and colleagues (Brain 2022), RT-QuIC sensitivity at standard cut-offs was 93 percent for E200K and 87 percent for V210I but 43 percent for P102L and 28 percent for fatal familial insomnia. A classification system that depends on a supporting test inherits that unevenness, which is why genetic forms can fail to reach the probable tier on tests that would reach it in sporadic disease. Diagnostic criteria as applied clinically are on diagnostic criteria and assay detail on diagnostics.

What does the classification leave open?

Three problems named by Manka and colleagues sit underneath the categories above. The replication mechanism is not precisely delineated. The molecular basis of strains and of inter-species transmission barriers is not explained in detail. And the neurotoxic PrP species has no structural definition, so the subtype labels describe the biochemistry of what propagates rather than the species that damages neurons.

A fourth problem is the boundary of the class itself. Prion mechanisms are now applied to other protein-misfolding neurodegenerative diseases, and research groups work on both, including the PRIONS team described on the mechanisms hub. Whether the templating and strain concepts transfer in full to those diseases is an open question rather than a settled extension.

Mechanisms hub, protein misfolding, neurotoxicity, open questions, and the plain-language versions what are prion diseases and more detail.

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