Fatal familial insomnia (FFI): research

FFI is the clearest demonstration in human prion disease that one mutation does not define one disease. It is also the subtype where the standard antemortem test performs worst, which has consequences for diagnosis, for surveillance counts and for trial recruitment. For the plain-language pages see fatal familial insomnia and its more detailed page.

Why does D178N produce two diseases?

Goldfarb and colleagues established the mechanism in 1992. FFI and a subtype of familial CJD, clinically and pathologically distinct, are linked to the same codon 178 mutation. Testing whether a second genetic component modifies expression, they found that the two phenotypes segregated with different haplotypes defined by the mutation together with the methionine-valine polymorphism at codon 129. The Met129-Asn178 allele segregated with FFI in all 15 affected members of five kindreds, and the Val129-Asn178 allele with the familial CJD subtype in all 15 affected members of six kindreds.

The key point is the allele carrying the mutation, not the overall genotype: the determining polymorphism is in cis with D178N. The sample is 30 affected people across eleven kindreds, which is small by current standards and has not been contradicted since.

What does a modern case series show about diagnosis?

Kortazar-Zubizarreta and colleagues screened the Basque Brain Bank database for patients diagnosed between 2010 and 2021 by standard genetic or neuropathological criteria, in a region with unusually high FFI incidence. The series has 16 patients, 12 of them from 9 unrelated but geographically linked kindreds, with 25 percent having no family history. Onset ranged from 36 to 70 years and disease course from 7 to 11.5 months.

Insomnia was the initial symptom in most cases, and polysomnography was consistent with the diagnosis in 92 percent. CSF 14-3-3 and CSF RT-QuIC were negative. Most patients were homozygous for methionine. Histopathology showed gliosis and neuronal loss in basal ganglia and thalamus, and western blotting identified PrPres type 2 preferentially, while RT-QuIC on brain tissue detected PrPSc more successfully than the CSF assay. The authors conclude that polysomnography and genetic study carry the highest diagnostic value among the tests analysed.

Two points deserve emphasis. A quarter of this series had no family history, so absence of a family history argues weakly against the diagnosis. And the negative CSF results are not a local laboratory artefact, as the next section shows.

Which substrate detects FFI seeds?

Myskiw and colleagues quantified the problem. In a retrospective panel of CSF from 61 sporadic CJD, 50 inherited prion disease and 5 VPSPr cases, end-point QuIC using a recombinant substrate derived from the North American deer mouse reached 96.6 percent sensitivity (111 of 116) and 100 percent specificity (35 of 35), against 87.1 percent for standard end-point QuIC with full-length hamster substrate and 72.4 percent for second-generation IQ-CSF RT-QuIC on the same cohort.

Within the inherited group, the FFI D178N cases were the extreme. The deer mouse substrate detected 12 of 13 with 1 indeterminate, the full-length hamster substrate 4 of 13 with 1 indeterminate, and the truncated hamster substrate used in IQ-CSF RT-QuIC detected none of 13. The authors report consistently longer lag phases for D178N seeds in both hamster-backbone substrates, and note that the same insensitivity for D178N, GSS, VPSPr and the VV1 sporadic subtype is seen at international testing centres. A human E200K-backbone substrate, proposed to improve detection in inherited disease, did not outperform the deer mouse or full-length substrates in their hands.

This is a substrate compatibility problem, not an absence of seeds. A negative second-generation RT-QuIC in a patient with insomnia and a family history should not be read as excluding FFI, and the laboratory running the assay should be asked which substrate it uses. Interpretation of any individual test result belongs with the treating neurologist and the testing centre; see how it is diagnosed.

What prion type is FFI?

Juergens-Wemheuer and colleagues analysed six FFI brains by western blot, a protein aggregate stability assay and paraffin-embedded tissue blotting. The unglycosylated protease-resistant fragment matched the size of sporadic CJD type 2 in every case. The reticular and synaptic deposition pattern instead resembled sporadic CJD type 1, and conformational stability against guanidine denaturation was also closer to type 1 than type 2. They conclude that fragment size is not a valid criterion on its own, and that FFI may constitute a prion type of its own sharing properties with both.

Six cases is a small series for a typing claim, and the Parchi 1999 classification the comparison uses was built for sporadic disease. The practical implication is that typing an inherited case by fragment size alone will place it in a sporadic category it does not biologically belong to.

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