PRNP M232R: research

Why is its status uncertain?

The general argument is set out at penetrance. Minikel and colleagues compared 16,025 prion disease cases against 60,706 population control exomes and 531,575 genotyped individuals, and found that PRNP missense variants previously reported as pathogenic were at least 30 times more common in the population than the prevalence of genetic prion disease predicts. They attribute part of that excess to benign variants falsely assigned as pathogenic and conclude that lifetime risks across these variants range from under 0.1 percent to about 100 percent.

M232R is one of the variants that discussion concerns, and nothing in the sources read for this page establishes a penetrance figure for it. The honest position is that carrying M232R is not equivalent to carrying D178N or E200K, and that a report describing it as a mutation does not by itself establish high risk. Interpretation of a result in a specific person requires a genetics service with access to the current classification; see counselling comes first.

What do the reported cases look like?

They are notable for missing the findings that usually support a diagnosis.

Tanaka and colleagues describe a 46-year-old man with an eight-month history of rapidly progressive dementia in whom diffusion-weighted MRI, EEG and amyloid PET showed no significant findings. CSF 14-3-3 protein was elevated and PRNP sequencing identified M232R, which the authors took as confirming hereditary CJD. Their framing is that the case was difficult to diagnose precisely because the characteristic investigations were unremarkable.

Lee and colleagues report a different presentation again: progressive ataxia with palatal tremor in a carrier of the M232R variation.

Miura and colleagues describe an 81-year-old man with compound heterozygous V180I and M232R in whom punctate diffusion-weighted hyperintensities appeared in bilateral frontal cortex and extended over three months, with cognitive decline beginning six months after the first scan. They characterise the course as relatively late in onset, slowly progressive, with infrequent periodic synchronous discharges, and present the pre-symptomatic MRI change as relevant to the development of new treatments.

Two cautions apply to this literature. Single case reports with a variant of uncertain significance cannot establish that the variant caused the illness, particularly where a second PRNP variant such as V180I is present, and a diagnosis resting on an elevated 14-3-3 together with a sequencing result is weaker than one resting on neuropathology or a positive amplification assay. No systematic series of M232R carriers appears in the sources read here.

What would settle it?

The design that resolved E200K and V210I is the one needed here: longitudinal follow-up of carriers identified by predictive testing, with deaths ascertained independently, compared against population life tables. That approach has been applied at the US surveillance centre to D178N, E200K and V210I, as described at E200K, and M232R is rare outside Japan, so the comparable work would have to come from Japanese surveillance data.

Related: the PRNP gene, variants, penetrance and codon 129.