Minikel EV et al. 2019, Age at onset in genetic prion disease and the design of preventive clinical trials (Neurology 93:e125-e134, PMID 31171647, doi 10.1212/WNL.0000000000007745)

This Neurology paper pooled age-at-onset or age-at-death data on 1,094 people with high-penetrance PRNP mutations from centres in several countries, and used it to ask how a preventive trial in healthy carriers could be designed. It found that onset ages are spread across several decades for the most common mutations, that sex, parental onset age and codon 129 do not help much in predicting onset, and that a trial using clinical onset as its endpoint would need hundreds or thousands of at-risk participants. The authors conclude that validated surrogate biomarkers are essential. The first and second authors were at the Broad Institute and the Prion Alliance; the last author is at the MRC Prion Unit. Bibliographic details were checked against Europe PMC and Crossref; the full text was only partly read. Information only, not medical advice.

Key facts

  • The paper is Minikel EV, Vallabh SM and 31 co-authors, "Age at onset in genetic prion disease and the design of preventive clinical trials", Neurology volume 93, issue 2, pages e125-e134, DOI 10.1212/WNL.0000000000007745, PMID 31171647.
  • It pooled age-at-onset or death data on 1,094 people with high-penetrance PRNP mutations; the main analysis used 1,001 people with the three most common mutations (E200K, P102L, D178N) from nine study centres.
  • Onset ages for the common mutations vary over several decades; for E200K the yearly onset hazard is only about 5 percent even at age 57, and for the three common mutations it stays under 10 percent until most carriers have died.
  • The next four most common mutations have tighter onset distributions but together make up about 10 percent of high-penetrance cases.
  • Sex, a parent's age at onset and the PRNP codon 129 genotype added no useful explanatory power for sorting trial participants.
  • A randomized preventive trial using clinical onset as endpoint would need hundreds or thousands of at-risk participants; the authors estimated only about 60 eligible people in the US (221 x 75 percent x 36 percent), which they call conservative and which rests on proportions borrowed from other data sets.
  • The authors identified 27 likely high-penetrance variants after reviewing 70 reported PRNP variants.
  • Recommendations are to find validated surrogate biomarkers, run longer trials with larger enrolment, and use historical controls in postmarketing studies to establish clinical benefit.
  • The introduction cites mouse work in which treatments given long before symptoms extended survival roughly 2 to 4 times, the case for testing prevention in carriers.
  • Funding listed in Europe PMC includes NIH institutes (NIAID, NIA, NINDS), the UK Medical Research Council, NIHR and Telethon.

Timeline

  1. 2018Manuscript received by Neurology.
  2. 2019Manuscript accepted.
  3. 2019Published online.
  4. 2019Print issue (Crossref date; Europe PMC gives July 2019).

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Last checked 1 November 2026

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