Gerstmann-Straussler-Scheinker disease (GSS): research

GSS sits apart from the rest of human prion disease biochemically. The protease-resistant species that accumulates comes from the middle of the prion protein rather than its C-terminal region, and several GSS alleles converge on that species. Plain-language pages: GSS and the more detailed version.

What is the shared biochemical pathway?

Mercer and colleagues worked from a young GSS patient whose mutation was an eight-residue duplication in the hydrophobic region, LGGLGGYV. They inserted the corresponding change into the wild-type mouse PrP gene and made transgenic lines, Tg.HRdup.

The mice developed spontaneous neurological syndromes, and brain extracts from them hastened disease in low-expressing Tg.HRdup mice, which the authors read as de novo prion formation. The mice showed spongiform change, PrP aggregates and the expected GSS hallmark of a proteinase K-resistant 8 kDa fragment from the centre of PrP. The insertion also altered the unstructured N-terminus, producing a 16 kDa species after thermolysin exposure, a plausible precursor of the 8 kDa fragment. Its presence in adolescent mice offers an explanation for the early disease of the index patient.

The generalising result is that the same 16 kDa thermolysin-resistant signature was found in patients carrying P102L, A117V, H187R and F198S, with coordinates similar to the GSS stop codon mutations. The authors conclude that this is a shared GSS pathway fundamentally distinct from the C-terminal structural changes seen in CJD and scrapie.

Caveats worth holding: the transgenic model expresses a mouse PrP carrying a human-derived change, spontaneous disease in overexpressing lines is not by itself proof of prion formation without the transmission step, and the patient signature was demonstrated in autopsy material across a small set of alleles.

Why do some GSS cases show tau pathology?

Matamoros-Angles and colleagues built induced pluripotent stem cell cultures from fibroblasts of a GSS patient carrying Y218N, a mutation with very few described cases, alongside an age-matched healthy control. One previously described case with this mutation had neurofibrillary degeneration with marked tau hyperphosphorylation.

The Y218N-derived cultures showed astrogliosis, increased phosphorylated tau, altered microtubule-associated transport and cell death. They did not generate proteinase K-resistant prion protein.

That dissociation is the useful part. A cellular model can reproduce the tauopathy seen in the patient without producing protease-resistant PrP, which argues that the tau changes are not a simple downstream consequence of PrPSc accumulation in this allele. It also means the model cannot be used to study prion propagation or to test compounds for effects on it.

Does GSS show up on antemortem CSF testing?

Better than FFI, and with the same substrate dependence. In the retrospective panel reported by Myskiw and colleagues, end-point QuIC with the deer mouse recombinant substrate detected all 10 P102L cases, against 8 of 10 with full-length hamster substrate and 4 of 10 with the truncated hamster substrate used in second-generation IQ-CSF RT-QuIC. The single P105S case was detected by both end-point assays and missed by IQ-CSF; the single A117V case was detected only by the deer mouse substrate. The authors state that low sensitivity for GSS is seen across international testing centres with current assays.

The sample sizes behind the rarer alleles are one case each, so those lines of the table indicate feasibility and nothing about population sensitivity.

What reproductive options are documented?

Uflacker and colleagues described preimplantation genetic diagnosis with IVF in a 27-year-old asymptomatic woman with a family history of GSS, which they report as the first such case in genetic prion disease. The cycles identified 6 embryos free of the F198S mutation, 2 of which were transferred, yielding a twin pregnancy and the birth of slightly premature infants with normal development at 27 months. The authors conclude that IVF with PGD is a viable option for couples wishing to avoid passing on the disease, and that neurologists should know of it in order to counsel at-risk families.

This is one case report, and it describes direct testing for a known family variant. Anyone considering this route needs genetic counselling first, and the rules on which conditions may be tested differ by country; see counselling comes first and the HFEA entry for the United Kingdom position. Not testing is a valid choice.

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