PRNP E200K: research

Are the prions the same as in sporadic CJD?

Barrio and colleagues tested this directly. Prion strains from E200K cases in Slovakia (12), Spain (9) and France (3) were characterised in transgenic mice expressing human PrP, across the genotypes E200K-Met129 with Met129, homozygous E200K-Met129, E200K-Met129 with Val129, and E200K-Val129 with Val129.

The strains corresponded to the two commonest sporadic strains, M1 and V2, present in individual patients either pure or in combination. The study also examined peripheral prion infectivity patterns, reporting low peripheral infectivity in these patients, which bears on the instrument and tissue questions covered at tissue and organs.

Strain identity with sporadic disease has an implication that is easy to miss: the mutation raises the probability of prion formation without creating a distinct agent, which is consistent with the general finding that the mutation influences susceptibility more than phenotype.

What does the pathology add?

In the genetic CJD classification series, E200K cases fell mainly into the 129M-type 1 group, with small non-confluent vacuoles and synaptic PrP deposition, and showed mutation-specific features: a thickened synaptic pattern of PrP deposits in the cerebellar molecular layer, laminar PrP immunoreactivity in deep cortical layers in E200K-129V carriers, and intraneuronal globular dots in E200K with the V2 or intermediate type. Eight patients carrying E200K-129M with valine on the wild-type allele showed an intermediate PrPSc type with a 20 kDa unglycosylated core, which the authors treat as a sixth group sharing traits with V2.

Kuru-type plaques, present in codon 129 heterozygous patients with octapeptide repeat insertions in the same series, were absent in heterozygous E200K patients, which is a useful discriminator at autopsy.

How penetrant is it?

Lower than the older literature implied. Lian and colleagues followed 99 initially asymptomatic carriers of pathogenic E200K at the US surveillance centre over more than 936 person-years and observed 18 deaths, significantly fewer than the 27.4 expected from life tables based on retrospective data. Age-dependent penetrance calculated from the longitudinal data was significantly lower than the retrospective estimate, at 69 percent by age 80, with a median age at death of 75.

Their summary is that E200K penetrance remains high, with the onset distribution shifted slightly later and lifetime risk slightly lower than previously reported, and that prospective data are needed to support preventive trials. The comparison against life tables is the weak joint in the analysis, since the expected number of deaths depends on the reference population and the ascertainment of the cohort. The direction of the correction, however, is important for anyone who was given an older figure: the earlier numbers came from affected families, where unaffected carriers are systematically under-recorded.

No penetrance figure describes a person. Risk conversations belong with a genetics service, and declining testing is a valid choice: see penetrance and the right not to know.

Why does E200K appear in diagnostic assays?

Because its sequence makes a useful substrate. Correia and colleagues report that a full-length human E200K recombinant protein gave the highest seeding efficiency of the substrates they tested in cerebrospinal fluid, raising sensitivity from 78 to 93 percent for symptomatic CJD and from 19 to 75 percent for fatal familial insomnia relative to a hamster-sheep substrate, and allowing detection in tear fluid.

A second group found no such advantage. In the panel reported by Myskiw and colleagues, a human E200K-backbone substrate did not outperform deer mouse or full-length hamster substrates, while all 7 E200K patient samples were detected by every substrate tested. E200K cases are among the easiest inherited cases to detect, so the substrate question is mainly relevant for the variants that are hard to detect, described at D178N.

Related: genetic prion disease, codon 129, the PRNP gene and variants.