PRNP D178N: research

How does the cis allele split the phenotype?

Goldfarb and colleagues tested whether a second genetic component modified expression of the codon 178 mutation. The Met129-Asn178 allele segregated with fatal familial insomnia in all 15 affected members of five kindreds, and the Val129-Asn178 allele with a familial CJD subtype in all 15 affected members of six kindreds.

The determining allele is the one carrying the mutation, in cis. A carrier’s overall codon 129 genotype does not settle which disease the variant will cause, which is why reports describe haplotypes such as D178N-129M rather than genotypes.

The histo-molecular classification of genetic CJD reproduces the same logic across mutations: PrPSc type together with the codon 129 allele on the mutated allele defines six phenotype groups that largely match the sporadic subtypes, with the mutation itself having a variable and overall smaller effect on phenotype while strongly influencing susceptibility. In that series D178N-129V cases showed intermediate-size vacuoles and an unglycosylated PrPSc band comprising a doublet including the 21 kDa type 1 peptide and a slightly faster-migrating fragment, a pattern also seen in sporadic VV1.

What is known about penetrance and age at death?

Lian and colleagues followed individuals who had positive antemortem PRNP genetic tests at the US National Prion Disease Pathology Surveillance Center, 404 people in total, using autopsy records and public record searches to establish vital status, with an estimated sensitivity of 92.6 percent for confirming deaths.

For D178N, the median age at death was 57, numerically later than in retrospective data but not significantly different. Their overall conclusion supports high penetrance for D178N and E200K and low penetrance for V210I, while calling for prospective data to support future preventive trials.

A median age at death is a cohort statistic. As the penetrance page sets out, age at onset in genetic prion disease varies across decades and is not predicted by sex, by a parent’s age at onset or by codon 129 genotype, so nothing here can be used to anticipate an individual course. Any discussion of personal risk belongs with a genetic counsellor; see counselling comes first.

Why does D178N defeat standard CSF testing?

This is the most consequential practical fact about the variant, and it is a substrate effect.

In the retrospective panel reported by Myskiw and colleagues, all 13 FFI D178N cases were negative with the truncated hamster substrate used in second-generation IQ-CSF RT-QuIC. End-point QuIC with full-length hamster substrate detected 4 of 13 with 1 indeterminate, and with the deer mouse substrate 12 of 13 with 1 indeterminate. The single D178N genetic CJD case in the same series was detected by both end-point formats and missed by IQ-CSF. The authors report consistently longer lag phases for D178N seeds in hamster-backbone substrates and note that the same insensitivity is seen at international testing centres.

A different group reached the same conclusion with a different substrate. Correia and colleagues report that a full-length human E200K recombinant substrate raised CSF sensitivity from 78 to 93 percent for symptomatic CJD and from 19 to 75 percent for fatal familial insomnia compared with the hamster-sheep substrate, and that the same assay detected amyloidogenic PrP in tear fluid with 85 percent sensitivity for sporadic CJD and 64 percent for symptomatic genetic prion disease.

Two independent routes to improving FFI detection both work by changing the substrate rather than the protocol. For a clinician, the question to ask a reference laboratory is which recombinant protein it runs, and a negative result on a hamster-backbone assay in a suspected D178N case carries little weight.

Related: fatal familial insomnia, codon 129, E200K and the PRNP gene.