The Generative Brain

Uflacker A et al. Preimplantation genetic diagnosis (PGD) for genetic prion disorder due to F198S mutation in the PRNP gene (JAMA Neurol 2014;71(4):484-486, PMID 24493558, PMC4349573)

A short case report in JAMA Neurology, April 2014, that the authors present as the first published use of in vitro fertilisation with preimplantation genetic diagnosis (PGD) to avoid passing on a genetic prion disease, here Gerstmann-Straussler-Scheinker disease caused by the PRNP F198S variant. It was written by psychiatrists at Duke University, reproductive genetics and IVF specialists in Chicago, and a neurologist and genetic counsellor at the UCSF Memory and Aging Center. The method used ICSI, sequential polar body testing and day-3 embryo biopsy, with linked markers as a check against known PCR error sources. Its message to neurologists is that PGD should be part of reproductive counselling for families with a PRNP variant. Later papers cite it as the reference that PGD is possible in genetic prion disease. This entry stays at method and publication level and records nothing about the people in the case. Information only, not medical or reproductive advice.

Key facts

  • Published in JAMA Neurology 2014;71(4):484-486 (doi 10.1001/jamaneurol.2013.5884) as a case report; the PMC copy is an NIH author manuscript (NIHMS636100) made available on 4 March 2015.
  • Six authors: Alice Uflacker (corresponding) and P Murali Doraiswamy of the Department of Psychiatry and Duke Institute for Brain Sciences; Svetlana Rechitsky of the Reproductive Genetics Institute, Chicago; Tricia See (genetic counsellor) and Michael Geschwind of the UCSF Department of Neurology, Memory and Aging Center; and Ilan Tur-Kaspa of the Reproductive Genetics Institute, the Institute for Human Reproduction and the University of Chicago department of obstetrics and gynecology.
  • Method as described: fertilisation by ICSI, then sequential testing of the first and second polar bodies for the familial variant, then day-3 blastomere biopsy to confirm results or fill gaps where polar body results were incomplete; testing was PCR based, run alongside linked markers flanking PRNP.
  • The authors name failed amplification, allele dropout of linked markers and recombination between markers and the variant as the sources of possible error that the combined approach is meant to guard against.
  • The report states that IVF with PGD is a viable option for couples who want to avoid passing on the disease, and recommends that neurologists discuss PGD with at-risk families and keep it in mind when advising on reproductive choices.
  • It describes non-disclosure PGD, in which the at-risk person does not learn their own genotype, as an available protocol, notes that predictive testing carries emotional risks, and points to Huntington disease PGD guidance as a model that other neurologic conditions might follow.
  • The authors list as limits that it is a single case with limited follow-up of offspring.
  • The Duke University School of Medicine IRB judged the report exempt, and written consent for publication was obtained.
  • Funding is stated two ways: a footnote says there was no external financial support for the report, while the acknowledgments list NIA grants R01 AG031189 and P50 AG023501, NCRR UCSF-CTSI UL1 RR024131, the Michael J. Homer Family Fund and ARCC grant 10-10030; Europe PMC also lists NINDS, NIA, NCRR and NCATS grants.
  • Disclosures: the IVF and PGD were carried out at the two Chicago centres that employ two of the authors, and one Duke author reports industry research grants, advisory fees and shareholdings unrelated to the report.
  • A companion comment by GN Wilson on presymptomatic and preimplantation diagnosis in neurology appeared in the same issue (pages 403-404).
  • Europe PMC lists 13 citing papers to 2026-10-17, mostly reviews of genetic prion disease and of PGD for neurological disorders, including a 2014 Nature Reviews Neurology perspective by two of the same authors and the 2022 Goldman and Vallabh counselling review; by title none is a further PRNP PGT case.
  • A 2019 French study of presymptomatic PRNP testing cites the report as the basis for saying prenatal or preimplantation diagnosis is possible, and reports in aggregate that some at-risk relatives saw PGD or prenatal testing as an option when they did not want to be tested themselves.

Timeline

  1. 2014Case report published in JAMA Neurology 71(4), with a companion comment in the same issue.
  2. 2014Tur-Kaspa, Jeelani and Doraiswamy perspective on PGD for inherited neurological disorders published online in Nature Reviews Neurology; it is among the citing papers.
  3. 2015Author manuscript released in PubMed Central.
  4. 2017UCSF genetic prion disease series (Takada and others, Geschwind last author) published, citing the report.
  5. 2019French psychological study of presymptomatic PRNP testing published, citing the report for PGD.
  6. 2022Goldman and Vallabh genetic counselling review published online, citing the report.
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