VV1 sporadic CJD

What is the reported phenotype?

Carrasco and colleagues summarise the published picture: an incidence of about one case per hundred million people a year, early average age at onset of 44 years, average duration of 21 months, absent periodic sharp wave complexes on EEG, and MRI hyperintensity in cerebral cortex with usually negative signal in basal ganglia and thalamus.

Their own case departed from that profile in several ways, which is the useful part of the report. Onset was at 61 years, duration 32 months, and RT-QuIC was negative. The presentation included paranoid thoughts and agitation, rapidly progressive memory decline, prosopagnosia, and late myoclonus and mutism. Antithyroid peroxidase antibodies were positive, which prompted a trial of high-dose steroids that did not help.

Areskeviciute and colleagues report a further case outside the reported profile: a 58-year-old woman with confirmed VV1 and a heterozygous one-octapeptide repeat deletion in PRNP, followed from symptom onset to death 22 months later. They note that most reported VV1 patients to date have been men with a mean onset age of 44, and that the absence of typical clinical and paraclinical features made brain biopsy necessary. Their stated conclusions are that clinicians should consider CJD in patients who do not meet the typical criteria, and that RT-QuIC needs adaptation for rare subtypes and for certain PRNP variants.

Two case reports cannot revise an average, and both were published because they were atypical. The honest reading is that the quoted onset age and duration come from small historical series and that individual cases span a wider range.

Why does the assay fail here?

Substrate, as in the inherited subtypes. The UK surveillance analysis cited on the subtypes hub found VV1 made up 32 percent of RT-QuIC negative definite sporadic CJD cases against 1 percent of positive cases.

Myskiw and colleagues tested the same problem with different substrates. All 5 VV1 cases in their panel were detected by end-point QuIC with either the deer mouse or full-length hamster substrate, while the truncated hamster substrate used in second-generation IQ-CSF RT-QuIC detected 2 of 5 with 1 indeterminate. They group VV1 with D178N, GSS and VPSPr as the categories where current assays perform poorly at international testing centres.

With five cases, that table shows feasibility rather than sensitivity. It does identify the variable to ask about when a clinically suspicious case tests negative: which recombinant substrate the laboratory used.

Why is distinguishing VV1 from variant CJD difficult?

Holper and colleagues describe a case whose clinical, epidemiological and radiological features initially raised concern for variant CJD, in which genetic testing, autopsy and neuropathology established VV1 sporadic CJD. Their argument is that the recent diagnosis of variant CJD in a codon 129 heterozygote removed the genotype shortcut, so distinguishing the two now needs the combined clinical, epidemiological, pathological, biochemical and radiological picture.

The stakes are asymmetric. A variant CJD diagnosis carries public health consequences, including questions about blood and tissue exposure, that a sporadic diagnosis does not; see blood and plasma. The same overlap problem arises from the MV2K side, at MV2.

Related: MM1, VV2, codon 129 and diagnostics.