Sporadic CJD subtypes

Which subtypes are recognised, and how common are they?

The 2026 Viruses review lists MM1, MM2-cortical, MM2-thalamic, MV1, MV2, VV1 and VV2. It names MM1 as the most common subtype and gives VV2 as about 15 percent of sporadic cases. The individual subtypes are described at MM1, MM2, MV1, MV2, VV1 and VV2.

The practical reason to record a subtype is that it predicts behaviour. Clinical duration, the pattern seen on MRI and EEG, the distribution of pathology and the sensitivity of each diagnostic assay all differ between them.

How does subtype affect whether a test is positive?

This is the best documented consequence. Ng and colleagues examined the 27 of 250 definite sporadic CJD cases, 10.8 percent, that were cerebrospinal fluid RT-QuIC negative in the United Kingdom surveillance programme. VV1 made up 32 percent of the negative group against 1 percent of the positive group, and MM2 21 percent against 3 percent. The negative patients were also younger at onset, with a median of 62 against 68 years, had longer disease duration, and were less likely to have gait difficulties, at 73 percent against 93 percent, or motor symptoms, at 62 percent against 80 percent. Co-occurring neurodegenerative disease was found in 9 of the 27. EEG and diffusion-weighted MRI sensitivity were similar in both groups.

Peripheral sampling shows the same dependence. Mammana and colleagues tested 71 skin punch biopsy samples from 35 CJD patients and reported 89 percent sensitivity and 100 percent specificity for skin prion RT-QuIC, with seeding activity higher in the subtypes associated with the V2 strain, VV2 and MV2K, than in typical MM1. They describe that observation as resting on a limited number of cases.

In the Myskiw and colleagues substrate comparison, the cases the authors grouped as atypical sporadic were VV1 with 5 samples, MM2 with 5 and variably protease-sensitive prionopathy with 5. Both end point formats detected all 5 VV1 and all 5 MM2 samples, while truncated hamster RT-QuIC detected 2 of 5 VV1 and 3 of 5 MM2, with indeterminate results in each group. The same paper has internal inconsistencies between its abstract and its tables, in both the case counts and the reported sensitivities, and the authors list independent validation and inter-laboratory reproducibility as outstanding. It is also worth noting that the paper places variably protease-sensitive prionopathy under an atypical sporadic CJD heading in Table 2 while its text describes it as a distinct disease; that classification is still being settled, and it is discussed at variably protease-sensitive prionopathy.

Can an assay tell the subtypes apart?

That is the aim of current substrate work rather than something already available. Marin-Moreno and colleagues reported in Microbiology Spectrum in 2025 that a recombinant human prion protein carrying the E219K polymorphism works as an RT-QuIC substrate. They amplified six sporadic CJD strains and the variant CJD strain from transgenic mouse brain homogenates and from patient samples, with rapid amplification across a wide dilution range, while one patient-derived strain, VV1, amplified over a narrower range. Lag times separated variant CJD from all the sporadic subtypes tested, which the authors present as a step towards strain typing before death.

That is the extent of what the published abstract supports. The detailed lag time ranges, the statistical model used for discrimination, the detection limits in femtograms, and the statements about spontaneous conversion in uninfected controls are reported in the full text, which did not open for this page, so they are not stated here. A reader relying on those figures should take them from the paper directly. The comparison across formats is collected in comparing the tests.

How stable is the classification?

Reclassification of archived material keeps finding cases the scheme does not accommodate. Areskeviciute and colleagues reclassified all definite prion disease cases with available fresh-frozen samples referred to the Danish Reference Center over 40 years, working with the Bologna prion group. They report rare sporadic CJD cases with mixed subtypes, subtypes with previously uncharacterised white matter plaques, one new case of sporadic fatal insomnia, and three novel PRNP variants comprising two large octapeptide repeat insertions and one point mutation. Methionine homozygotes at codon 129 were more prevalent among patients than in the general population, consistent with other cohorts of European ancestry.

Mixed subtypes within one brain are the awkward finding for a two-part code, because they indicate that a case need not have a single subtype.

Is any subtype linked to an animal source?

This remains an open experimental question rather than a finding. IRTA-CReSA announced in January 2018 a project funded in part by the Spanish Ministry of Economy and Competitiveness, reference AGL2017-88353-P, led by Enric Vidal with Montserrat Ordonez, studying a possible causal relationship between sporadic CJD cases and scrapie of small ruminants. The human material is five cases: three sporadic CJD cases of the MM1, MV2 and VV2 subtypes diagnosed in Catalonia, and two variably protease-sensitive prionopathy cases of the MM and MV genotypes diagnosed in the Basque Country. The method is serial intracerebral inoculation into two transgenic mouse lines expressing ovine and caprine prion protein, Tg338 with the VRQ genotype and Tg501 with ARQ, followed by neuropathological and biochemical characterisation, with protein misfolding cyclic amplification in small ruminant substrates used to speed adaptation before in vivo work.

The news item cites a 2014 Nature Communications study by Cassard and colleagues in which transgenic mice overexpressing human cellular prion protein, inoculated with several classical sheep scrapie isolates, developed a phenotype identical to that produced by sporadic CJD isolates. The item states that this does not prove scrapie ingestion causes sporadic CJD, while taking it as showing that the barrier between ovine and human prions is not absolute, so a zoonotic origin for some cases cannot be ruled out. No results from the IRTA-CReSA project are reported in that item. The species barrier evidence is set out in transmission and biosafety.

The disease as a whole is covered in sporadic CJD research.