PRNP V180I

Why is it often mistaken for Alzheimer’s disease?

Because memory and thinking change first and the dramatic features come late or not at all. Qina and colleagues analysed 186 patients from Japanese national surveillance between 1999 and 2013. Cognitive impairment was the dominant early symptom. Myoclonus, the sudden involuntary muscle jerk that is common in sporadic Creutzfeldt-Jakob disease, occurred in about 35 percent of patients with the commonest codon 129 genotype, against 88 percent of the sporadic comparison group. The EEG pattern of periodic sharp waves that supports a Creutzfeldt-Jakob diagnosis appeared in under 8 percent, against more than 90 percent of the comparison group.

The authors state directly that these patients tended to be misdiagnosed as dementia due to Alzheimer’s disease.

Two things do point towards a prion disease. MRI showed bright areas in the cortex in almost every patient scanned, 99.3 percent in the larger genotype group, which the authors describe as a diffuse cortical pattern that nonetheless overlaps with sporadic disease. And the course, averaging about two to three years, is faster than a typical Alzheimer’s course and slower than sporadic Creutzfeldt-Jakob disease.

What do the spinal fluid tests show?

Less than in sporadic disease. In the same series, spinal fluid 14-3-3 was positive in about 87 percent of patients in the larger genotype group and 61 percent in the smaller one, total tau in about 91 and 67 percent, and the prion protein test in about 68 and 39 percent, against 90 percent in the sporadic comparison group. Total tau levels were lower than in sporadic disease.

The authors conclude that because the prion protein result is positive in so few patients, genetic analysis is often needed to separate this illness from a slowly progressive dementia. A negative spinal fluid result therefore does not settle the question, which is the same caution set out on tests explained.

Why does nobody else in the family have it?

Because most people who carry this change do not become ill. In the 186 patients, only 11, about 6 percent, had any family history of dementia. The authors describe that as very low penetrance, penetrance being the proportion of carriers who develop the illness during a lifetime.

Published estimates put the figure for V180I at around 1 percent, which the 2022 review by Appleby and colleagues repeats, grouping V180I and V210I as low penetrance variants. Those estimates come from comparing how often the change appears in patients with how often it appears in large population databases. Two cautions belong with them. The figure is an average across a population, not a prediction for a person, and a low average is not reassurance for anyone in particular. Appleby and colleagues also note that an absent family history in genetic prion disease can itself be a consequence of low penetrance, so a relative who says the family has no history of this illness may be describing exactly this situation.

Interpretation for your family belongs with a genetic counsellor and the laboratory that issued the report. Counselling comes first describes those appointments, and nothing here is advice about anyone’s own risk.

Why is it so much commoner in Japan?

Nobody has published an explanation. What is established is the pattern: V180I is the commonest variant in Japanese genetic prion disease and uncommon in European and North American series. The Japanese data are therefore the only large clinical description available, and whether the same picture appears in families elsewhere has not been tested in a series large enough to say.

This uneven distribution has a practical effect. A laboratory in a country where the variant is rare may have classified it from the published literature rather than from local cases, so the report’s wording about pathogenicity is worth discussing with the issuing laboratory rather than reading as settled.

How does late onset change what a family decides?

It changes the arithmetic of a predictive test. For a variant that begins in the late seventies and affects a small minority of carriers, a positive result in a healthy person in their forties describes a possibility decades away. Goldman and Vallabh, writing on genetic counselling for prion disease, note that someone who tests positive may differ from other family members in both age at onset and presentation, and they set out options between testing and not testing, including banking DNA from an affected relative and holding a result in reserve rather than receiving it.

Testing is voluntary. The Australian national registry states that plainly and recommends consultation with a genetic service. Choosing not to test is a position people hold for years, and the right not to know covers it.

What is not settled

The largest series was retrospective and built from surveillance records, so the symptom frequencies in it depend on what clinicians recorded at the time. The authors state that the reasons for the later onset and slower course are unclear. No prospective cohort has been published, and the penetrance figure of about 1 percent rests on a method its own authors describe as imperfect because populations differ in ways that are hard to match. A clinician reading a V180I result in an older patient with a slowly progressive dementia should treat the low rate of positive spinal fluid tests as the finding most likely to mislead.

Neighbouring pages are the variants hub, V210I, which carries a higher estimated risk and also usually appears without a family history, and protective variants, where the codon 219 allele is also concentrated in East Asia.