Genetic prion diseases are a rare and diverse group of fatal neurodegenerative disorders
caused by pathogenic sequence variations in the prion protein gene, PRNP. Data on
CSF biomarkers in patients with genetic prion diseases are limited and conflicting
results have been reported for unclear reasons. Here, we aimed to analyse the diagnostic
accuracy of CSF biomarkers currently used in prion clinical diagnosis in 302 symptomatic
genetic prion disease cases from 11 prion diagnostic centres, encompassing a total
of 36 different pathogenic sequence variations within the open reading frame of PRNP.
CSF samples were assessed for the surrogate markers of neurodegeneration, 14-3-3 protein
(14-3-3), total-tau protein (t-tau) and alpha-synuclein and for prion seeding activity
through the real-time quaking-induced conversion assay. Biomarker results were compared
with those obtained in healthy and neurological controls. For the most prevalent PRNP
pathogenic sequence variations, biomarker accuracy and associations between biomarkers,
demographic and genetic determinants were assessed. Additionally, the prognostic value
of biomarkers for predicting total disease duration from symptom onset to death was
investigated. High sensitivity of the four biomarkers was detected for genetic Creutzfeldt-Jakob
disease associated with the E200K and V210I mutations, but low sensitivity was observed
for mutations associated with Gerstmann-Straussler-Scheinker syndrome and fatal familial
insomnia. All biomarkers showed good to excellent specificity using the standard cut-offs
often used for sporadic Creutzfeldt-Jakob disease. In genetic prion diseases related
to octapeptide repeat insertions, the biomarker sensitivity correlated with the number
of repeats. New genetic prion disease-specific cut-offs for 14-3-3, t-tau and alpha-synuclein
were calculated. Disease duration in genetic Creutzfeldt-Jakob disease-E200K, Gerstmann-Straussler-Scheinker-P102L
and fatal familial insomnia was highly dependent on PRNP codon 129 MV polymorphism
and was significantly associated with biomarker levels. In a large cohort of genetic
prion diseases, the simultaneous analysis of CSF prion disease biomarkers allowed
the determination of new mutation-specific cut-offs improving the discrimination of
genetic prion disease cases and unveiled genetic prion disease-specific associations
with disease duration.
