PRNP V210I: research

How often is there no family history?

In the German surveillance comparison (Schelzke, Kretzschmar and Zerr, European Journal of Epidemiology 2012), none of 16 V210I patients had a positive family history of prion disease. In the same report, 47 percent of 23 E200K patients had at least one other affected relative. Thirteen of the 16 V210I patients were codon 129 MM and 3 MV, with the variant linked to the methionine allele in all cases.

This fits the penetrance estimate rather than contradicting it. Minikel and colleagues (Science Translational Medicine 2016) put lifetime risk near 10 percent for V210I from population-matched allele frequencies, and Appleby and colleagues (Frontiers in Neurology 2022) repeat that figure. At that level most carriers in a pedigree are unaffected, so most affected people present as apparent isolated cases. The estimate is a population average, described by its authors as imperfect because of population stratification, and it is not a statement about any individual. Interpretation of a result belongs with a genetic counsellor and the reporting laboratory.

Across genetic prion disease as a whole, E200K, V210I, V180I, P102L and D178N together account for about 85 percent of cases, as stated in the Sardinian R208H series (Neurogenetics 2020).

How closely does it resemble sporadic CJD?

Closely, on every axis the German report measured. V210I patients and sporadic CJD controls matched for age, sex and codon 129 genotype did not differ significantly in 14-3-3 positivity, CSF tau level, EEG or MRI. Age at onset was 63 years, range 45 to 80, and disease duration 6 months, range 1 to 20. Symptoms at onset in V210I against matched sporadic controls were prodromal 75 against 81 percent, dementia 69 against 69 percent, cerebellar 63 against 75 percent, myoclonus 25 against 19 percent, pyramidal 13 against 31 percent, extrapyramidal 31 against 6 percent, psychiatric 13 against 25 percent and sensory 19 against 6 percent.

CSF 14-3-3 was positive in all 16. Median CSF tau was 7,640 pg/ml, with no difference between MM and MV subgroups, 7,628 against 7,686 pg/ml, P = 0.991. Periodic sharp wave complexes appeared on EEG in 44 percent, and white matter lesions on MRI in 30 percent, fewer than the 60 percent seen in the E200K group.

The report is a letter from one surveillance unit with 16 V210I patients, 3 of them MV, and the two mutation groups were not matched to each other, so comparisons between E200K and V210I in it are confounded. PrP type was unavailable for most cases. Its text and tables disagree on several values, including the V210I sex ratio and the sporadic CJD tau medians.

What do the larger biomarker data show?

Schmitz and colleagues (Brain 2022) had 47 V210I cases from 11 centres, the second largest variant group after 112 E200K cases. Codon 129 was MM in 34, MV in 11 and VV in 2. Using standard sporadic CJD cut-offs, sensitivity was 79 percent for 14-3-3 by western blot, 94 percent for 14-3-3 by ELISA, 96 percent for total tau, 96 percent for alpha-synuclein and 87 percent for RT-QuIC. Those are the highest figures for any variant group in that cohort, above E200K at 70 to 93 percent and far above P102L at 14 to 43 percent. Areas under the curve against healthy controls were 1.0 for 14-3-3, 0.99 for total tau and 1.0 for alpha-synuclein.

The variant-specific cut-offs the authors derived for V210I are higher than the sporadic ones, not lower: against healthy controls, 14-3-3 above 9,706 AU/ml, total tau above 431 pg/ml and alpha-synuclein above 624 pg/ml, each at 96 to 100 percent sensitivity; against neurological disease controls, 14-3-3 above 39,695 AU/ml, total tau above 2,071 pg/ml and alpha-synuclein above 1,389 pg/ml, each at 94 percent sensitivity and 99 to 100 percent specificity. The authors note that these cut-offs were derived and evaluated in the same retrospective cohort, which may bias the accuracy estimates.

Myskiw and colleagues (Annals of Neurology 2026) tested 2 archived V210I CSF samples, positive in 2 of 2 on all three assay formats, including the truncated hamster IQ-RT-QuIC that missed most P102L and all fatal familial insomnia samples. Two cases is not a sensitivity estimate, and the direction agrees with the larger cohort.

What predicts duration?

In the Brain 2022 cohort, median duration from onset to death in V210I was 4.0 months, interquartile range 3.0 to 6.9, the shortest of the four groups analysed, against 6.0 months for E200K, 12.0 for fatal familial insomnia and 57.7 for P102L. The hazard ratio for V210I against fatal familial insomnia was 2.3580, P less than 0.001, and against E200K 1.2928, P = 0.528.

Codon 129 genotype showed no effect on duration in V210I, P = 0.6226, which separates it from E200K and fatal familial insomnia, where MV cases lived significantly longer. Instead younger age at onset, hazard ratio 1.0587, P = 0.0016, and male sex, hazard ratio 1.9972, P = 0.0360, predicted shorter duration. Those two associations come from one retrospective cohort, were found alongside many other tests, and the authors list multiple testing among their limitations.

What this means for case finding

Two findings sit together: V210I disease looks like sporadic CJD on clinical and biomarker grounds, and affected people generally have no family history to prompt genetic testing. A clinician’s threshold for sequencing PRNP in apparently sporadic rapidly progressive dementia is therefore what determines how many V210I cases are identified, and the published series do not establish what that threshold should be.

Related pages: A117V, V180I, penetrance, the variants hub and the plain-language V210I explained.