VV2 sporadic CJD

What distinguishes the pathology?

In the 300-case series, the ataxic and kuru-plaque variants together accounted for 25 percent of cases and were associated with type 2 protein and with valine homozygosity or heterozygosity respectively, with ataxia the presenting feature of the valine homozygous group.

The lesion distribution is the clearest difference from MM1. Work on the genetic counterparts of these groups describes the valine-type 2 profile as predominantly involving limbic cortices, deep brain nuclei and midbrain, with variable cerebellar involvement and neocortical change less severe than the subcortical change, particularly in the occipital lobe. Cortical spongiform change in this group consists of non-confluent vacuoles of intermediate size, often laminar with deeper layers predominantly affected. That description comes from the genetic CJD series, where the authors state the pattern reproduces what is seen in sporadic VV2 and MV2K.

In the mixed-type study, the type 2 phenotype prevailed in valine homozygotes, and molecular typing was the better method for detecting concurrent PrPSc types in these patients, where neuropathology was better in methionine homozygotes.

What does molecular profiling add?

Tarozzi and colleagues compared MM1 and VV2 by targeted sequencing of 118 genes in 48 CJD patients and exome RNA sequencing of post-mortem frontal cortex in a subset. VV2 was associated with greater impairment of pathways related to dopamine secretion, regulation of calcium release and GABA signalling, with similarities to Parkinson disease at both genomic and transcriptomic levels, while MM1 showed no distinctive signature. The integrated analysis also identified ADAR-mediated RNA editing sites, extending animal model findings.

The cohort is small, and frontal cortex in VV2 is relatively spared compared with the subcortical structures, so the tissue sampled is not where this subtype does most of its damage. The subtype contrast within one pipeline is what the study supports.

Why is VV2 easier to detect in some assays?

Seeding efficiency differs by strain and substrate. Belondrade and colleagues assessed PMCA of PrPTSE from 14 sporadic CJD brains in three substrates and found strong seed and substrate dependence across the five major subtype groups, with valine 129 human PrP substrate more permissive than methionine 129 substrate, and bank vole substrate propagating all subtypes while preserving the molecular type. They state that the sensitivity needed to detect VV2 prions in cerebrospinal fluid was achieved.

The same direction appears in peripheral sampling. As noted on the subtypes hub, skin prion RT-QuIC showed higher seeding activity in the subtypes associated with the V2 strain, VV2 and MV2K, than in typical MM1, on a limited number of cases.

What unusual presentations are reported?

Ong and colleagues describe two patients with progressive cognitive decline who had peripheral nerve hyperexcitability on electrodiagnostic testing, a finding usually associated with autoimmune or paraneoplastic syndromes with antibodies against the voltage-gated potassium channel complex. In both, those antibodies were negative and autopsy confirmed VV2 sporadic CJD. Their recommendation is to consider sporadic CJD in patients presenting with peripheral nerve hyperexcitability and rapidly progressive dementia. A separate report describes agrypnia excitata, a sleep and autonomic syndrome more often linked to thalamic disease, in a VV2 patient.

These are two patients and one case report. They widen the differential rather than describing a typical course, and no inference about an individual patient’s symptoms can be drawn from them.

Related: MM1, MV2, VV1 and scrapie, where the VV2 subtype appears in cross-species transmission panels.