Variably protease-sensitive prionopathy (VPSPr): more detail

How was it defined, and on what evidence?

It was first reported in 2008 as protease-sensitive prionopathy, from a re-examination of suspected cases referred to the US National Prion Disease Pathology Surveillance Center between 2002 and 2010, and renamed variably protease-sensitive prionopathy in 2010.

The defining finding is molecular. The 1E4 antibody reveals a ladder-like profile of about five fragments, at roughly 26, 23, 20, 17 and 7 kDa, which the 2013 update calls the pathognomonic molecular feature; the commonly used 3F4 antibody detects it poorly. That antibody dependence is the practical reason the entity went unrecognised, and the reason cases are still likely to be missed where 1E4 is not used.

The first report described 11 cases, a 2010 study examined 15, and the 2013 update cited 26 reported cases in total. Merck’s professional reference, fully reviewed in May 2026, gives an incidence of 1 to 2 per 100 million. Every figure below rests on series of this size.

What is the clinical phenotype?

Average age at onset is 70. Presentation is with psychiatric symptoms, speech deficits including aphasia or dysarthria, and cognitive impairment, with ataxia and parkinsonism developing later. Survival is given as 24 months. The 2013 update describes an atypical phenotype with a Gerstmann-Straussler-Scheinker-like picture and long disease duration without stating a median.

A family history of dementia is reported in approximately 42 percent of patients, and 8 of the 26 cases in the 2013 update had one. No mutation has been found in the PRNP open reading frame in these patients. The association is unexplained and should not be presented to a family as evidence of heritability; dementia of other causes is common in this age group. Where a family pattern is a concern, the route is clinical genetics rather than inference from this literature. PRNP variants and genetic counselling comes first set out that pathway.

What does the neuropathology show?

Moderate spongiform degeneration with PrP immunostaining, and in the cerebellum dot-like staining or small plaque-like formations, without the multicentric plaques characteristic of GSS. Target-like and plaque-like deposition patterns are described. The tissue diagnosis rests on 1E4 western blotting alongside haematoxylin and eosin staining and immunohistochemistry.

Why do the standard investigations fail?

Because they are calibrated on sporadic CJD. MRI, EEG and CSF 14-3-3 and total tau are usually not helpful in VPSPr. CSF RT-QuIC is positive in some cases and is less sensitive than in sporadic CJD.

The 2026 Canadian assay comparison quantified that on 5 VPSPr samples within a 116-sample panel: 3 of 5 positive with the modified deer mouse end-point assay, 3 of 5 with the standard hamster end-point assay and 2 of 5 with one indeterminate by IQ-CSF RT-QuIC. VPSPr improved least of any group, while the same modified assay lifted overall sensitivity to 96.6 percent. The US reference centre quotes CSF RT-QuIC sensitivity of 90.3 percent and specificity of 98.5 percent for prion disease generally, and that figure should not be applied to a suspected VPSPr case.

The implication for practice is that a negative CSF panel does not exclude VPSPr, and that neuropathological examination with the appropriate antibody is what confirms or refutes it. Where the question arises in life, early contact with the national surveillance centre determines whether the right investigations are arranged and whether post-mortem examination can be offered to the family. How prion disease is diagnosed covers the panel.

What is known about transmissibility?

Transmission appears limited. Humanised mice inoculated with VPSPr 129VV brain showed no clinical disease over a normal lifespan, and fewer than 20 percent developed scattered PrP plaques with minimal or no spongiform change. Preliminary bank vole data linked transmissibility to the vole codon 109 polymorphism. PMCA amplification was much lower than for iatrogenic or sporadic CJD, reported as unpublished data in the 2013 update.

This is laboratory transmissibility in model systems, which is not a statement about risk to people in contact with a patient. The general position holds: there is no evidence of person-to-person transmission of human prion disease through ordinary social or clinical contact, and standard infection control applies to routine care, with additional precautions for procedures involving brain, spinal cord or posterior eye tissue.