MV2 sporadic CJD

What does the largest series show?

Baiardi and colleagues characterised 126 patients, assessing neurological histories, CSF biomarkers, MRI and EEG alongside regional PrPSc typing, histology and PrP immunohistochemistry.

Mean disease duration was 18.0 months, against 3.4 months in typical MM1, and duration correlated positively with the severity of pathological change and with the number of cerebellar kuru plaques. Onset and early disease featured prominent and often mixed cerebellar symptoms with memory loss, variably accompanied by behavioural, psychiatric and sleep disturbance.

Investigation yields were as follows. CSF RT-QuIC was positive in 97.3 percent of cases, CSF 14-3-3 in 52.6 percent and total tau in 75.9 percent. Diffusion-weighted MRI showed hyperintensity of the striatum in 81.4 percent, cerebral cortex in 49.3 percent and thalamus in 33.8 percent, with a typical profile in 92.2 percent. EEG showed periodic sharp wave complexes in only 8.7 percent.

The combination explains why this subtype is called atypical while remaining diagnosable. The classic EEG finding is almost absent and the surrogate CSF markers are unreliable, while the amplification assay and DWI both perform well. The authors’ conclusion is that consistent use of RT-QuIC and DWI allows accurate early clinical diagnosis in most of these patients.

What is the molecular signature?

Systematic regional typing revealed a western blot profile with a doublet of unglycosylated fragments at 19 and 20 kDa, the 19 kDa band more prominent in neocortex and the 20 kDa band in the deep grey nuclei. The ratio of the 20 kDa to the 19 kDa fragment correlated positively with the number of cerebellar kuru plaques.

This is why a single region is not enough to type an MV2K case. The mixed-type study made the same point from the other direction: in MV cases with kuru plaques, molecular typing detected concurrent PrPSc types better than neuropathology did, while in MM cases neuropathology was the more sensitive method.

Coexisting MV2-cortical features changed the imaging. Mixed histotypes showed abnormal cortical signal more often than pure MV2K cases, 64.7 against 16.7 percent, P equal to 0.007.

Where does it resemble variant CJD?

Closely enough to require care. Bosnjak and colleagues report an MV2K case with florid-like plaques on routine histology, though sparse and regionally restricted compared with variant CJD, in a patient with a prolonged isolated psychiatric prodrome, new onset limb pain and late cognitive decline. They note that the description of a variant CJD case in a codon 129 heterozygote removes the genotype argument that previously separated the two, and recommend complementary diagnostic methods rather than histology alone.

This matters beyond the individual diagnosis, because a variant CJD case triggers a public health response that a sporadic case does not. The equivalent problem for the VV1 subtype is described at VV1.

How variable is the pathology?

Iwasaki and colleagues describe an autopsy-confirmed MV2K case with extensive fine vacuole spongiform change in the cerebral cortex, more pronounced in deeper layers, with numerous cerebellar kuru plaques, diffuse synaptic and perineuronal PrP deposition, and no periodic sharp wave complexes on EEG. The patient presented with gait ataxia, later cognitive dysfunction and a startle reaction without myoclonus, and died at 61 after 13 months without reaching akinetic mutism. Another reported case, from the same group’s wider literature, showed prominent thalamic DWI hyperintensity.

Single cases establish the range rather than the rule. The useful summary for a clinician is that cerebellar onset with a long course, striatal DWI change and a positive RT-QuIC fits this subtype, and that a negative EEG and a negative 14-3-3 do not count against it.

Related: MM1, MM2, VV2 and variant CJD.