PRNP V180I: research

How common is it, and where?

In Japanese national surveillance over ten years (Nozaki and colleagues, Brain 2010), 216 of 1,222 prion disease patients had genetic prion disease. V180I was the commonest variant in that group at 41.2 percent, ahead of P102L at 18.1 percent, E200K at 17.1 percent and M232R at 15.3 percent. The authors note that V180I and M232R are rare worldwide.

The international multicentre biomarker cohort of Schmitz and colleagues (Brain 2022), drawing on 11 European and other prion centres, contained 1 V180I case against 112 E200K and 47 V210I. That contrast is a reasonable proxy for how unevenly the variant is distributed.

What penetrance do population controls support?

Minikel and colleagues (Science Translational Medicine 2016) estimate lifetime risk near 1 percent for V180I from allele frequencies matched by population. Appleby and colleagues (Frontiers in Neurology 2022) repeat that 1 percent figure. The method is described by its authors as imperfect because of population stratification, and the estimate is a population average rather than an individual risk. The same analysis places baseline lifetime prion disease risk in the general population at about 1 in 5,000, so the V180I estimate is an elevation of roughly fifty-fold on a low baseline. Interpretation for a family belongs with a genetic counsellor and the reporting laboratory.

The low penetrance explains a clinical observation in the Japanese series: of 186 patients, 11, or 5.9 percent, reported any family history, and only 3 had a relative with CJD. A V180I result in a patient with no affected relatives is the usual pattern rather than an anomaly.

What is the clinical picture?

Qina and colleagues (BMJ Open 2014) analysed 186 V180I patients from the Japanese Prion Disease Surveillance Committee, April 1999 to September 2013, with definite or probable genetic prion disease by WHO criteria. Codon 129 was typed in 184: MM in 139, or 75.5 percent, and MV in 45, or 24.5 percent. There were 78 men and 108 women.

Mean age at onset was 77.2 years, standard deviation 6.9, against 68.9 years, standard deviation 9.1, in their sporadic CJD MM1 comparison group of 59 patients, P less than 0.001. Mean disease duration in codon 129 MM patients was 23.1 months, standard deviation 15.1, n = 75, against 17.2 months, standard deviation 12.5, in the comparison group, P = 0.032.

Cognitive impairment was universal in both groups. Every other classic feature was less frequent in V180I than in the sporadic comparison group, in codon 129 MM patients:

Extrapyramidal signs were similar in the two groups, 53.4 percent against 57.7 percent. In the codon 129 MV subgroup, myoclonus at 48.8 percent and akinetic mutism at 68.2 percent were more frequent than in the MM subgroup, while pyramidal signs at 33.3 percent were less frequent. The paper reports 7.3 percent for periodic sharp wave complexes in its text and 7.6 percent in its table, and 8.3 percent for overall visual disturbance against 9.2 percent in the MM subgroup.

MRI hyperintensity was present in 135 of 136 MM patients scanned and all 44 MV patients, described as a cortical ribbon pattern that overlaps with sporadic CJD MM1.

How do CSF tests behave?

In the Japanese series, CSF 14-3-3 was positive in 46 of 53 MM patients tested, 86.8 percent, and total tau in 48 of 53, 90.6 percent, close to the sporadic comparison figures of 87.1 percent for both. Median total tau was lower, 2,400 pg/mL against 5,450 pg/mL, P less than 0.001. CSF PrPSc was positive in 36 of 53 MM patients, 67.9 percent, against 90.0 percent in the comparison group, and in only 7 of 18 MV patients, 38.9 percent. The authors state that because of this low positivity, genetic analysis was often needed to separate V180I disease from slowly progressive dementia.

Two later studies each contain a single V180I case, and they point in opposite directions on seeded conversion assays. Schmitz and colleagues report their one V180I case as positive on 14-3-3, total tau and alpha-synuclein and negative on RT-QuIC. Myskiw and colleagues (Annals of Neurology 2026) report their one V180I case as positive on the truncated hamster IQ-RT-QuIC format and negative on both EP-QuIC formats, and note it was the only case in their study detected by IQ-RT-QuIC and missed by EP-QuIC. One case each is not a sensitivity estimate. What both results share, with the 67.9 percent figure above, is that a negative seeding assay does not exclude V180I disease.

What is unresolved

The authors of the 186-patient series state that their work was retrospective and focused on clinical features, and that the mechanisms behind the later onset and slower course are unclear. No prospective V180I cohort has been published in the sources opened here, and no clinical series outside Japan is large enough to say whether the phenotype travels.

Related pages: protective variants, where the codon 219 lysine allele is also East Asian in distribution, V210I, penetrance and the plain-language V180I explained.