Preimplantation Genetic Diagnosis (PGD) for Genetic Prion Disorder Due to F198S Mutation in the PRNP Gene | Genetics and Genomics | JAMA Neurology | JAMA Network
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Case Report/Case Series
April 2014

Preimplantation Genetic Diagnosis (PGD) for Genetic Prion Disorder Due to F198S Mutation in the PRNP Gene

Author Affiliations
  • 1Department of Psychiatry and the Duke Institute for Brain Sciences, Duke University, Durham, North Carolina
  • 2Reproductive Genetics Institute, Chicago, Illinois
  • 3Department of Neurology, Memory and Aging Center, University of California, San Francisco
  • 4InformedDNA, Informed Medical Decisions Inc, St Petersburg, Florida
  • 5Department of Obstetrics and Gynecology, The University of Chicago
  • 6Institute for Human Reproduction, Chicago, Illinois
JAMA Neurol. 2014;71(4):484-486. doi:10.1001/jamaneurol.2013.5884

Importance  To describe the first case of preimplantation genetic diagnosis (PGD) and in vitro fertilization (IVF) performed for the prevention of genetic prion disease in the children of a 27-year-old asymptomatic woman with a family history of Gerstmann-Sträussler-Sheinker syndrome (GSS).

Observations  PGD and fertilization cycles resulted in detection of 6 F198S mutation-free embryos. Of these, 2 were selected for embryo transfer to the patient’s uterus, yielding a clinical twin pregnancy and birth of healthy but slightly premature offspring with normal development at age 27 months.

Conclusion and Relevance  IVF with PGD is a viable option for couples who wish to avoid passing the disease to their offspring. Neurologists should be aware of PGD to be able to better consult at-risk families on their reproductive choices.

Quiz Ref IDPreimplantation genetic diagnosis (PGD) with in vitro fertilization (IVF) has emerged as an important option for at-risk couples wishing to conceive a healthy child without a fatal or severely debilitating inherited disorder.1,2 PGD allows for transferring only embryos without the disease-causing mutation into the uterus.1,2

Quiz Ref IDPrion diseases, also termed transmissible spongiform encephalopathies, are a group of fatal neurodegenerative disorders linked to abnormal folding of the prion protein.Quiz Ref IDGenetic prion diseases (gPrDs) are divided into 3 forms based on clinicopathologic features: familial Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal familial insomnia. There is currently is no cure, and the illness is uniformly fatal. One genetic mutation linked to GSS is a phenylalanine to serine change at codon 198 (F198S) in the prion protein gene (PRNP), which has known high penetrance.3 We describe the first application to our knowledge of PGD for a patient carrying the F198S mutation for the gPrD GSS.

Report of a Case

This case report was deemed exempt research by the Duke University School of Medicine institutional review board, and the patient gave written permission for this report.

A 27-year-old asymptomatic woman with a known family history of GSS chose to undergo predictive testing after genetic counseling and was identified with an F198S PRNP mutation with codon 129VM (V cis) polymorphism. The patient opted to be informed of the results of her genetic test. During prior genetic counseling, PGD had been presented as an option, and she and her husband chose to have PGD at a private experienced IVF and PGD center.

After providing written informed consent, the patient underwent IVF-PGD cycles, using methods reviewed elsewhere.2,4 Twelve of 14 mature retrieved oocytes were fertilized by intracytoplasmic sperm injection and were available for testing (Figure). PGD by sequential polar body 1 (PB1) and polar body 2 (PB2) mutation analysis, followed by additional blastomere analysis of day-3 embryos and confirmation, identified 6 mutation-free embryos (Nos. 1, 2, 3, 7, 10, and 14) (Figure).

Figure.  Preimplantation Genetic Diagnosis (PGD) for Gertmann-Sträussler-Scheinker Syndrome (GSS) Determined by an Autosomal Dominant Mutation in the Prion Protein Gene (PRNP)
Preimplantation Genetic Diagnosis (PGD) for Gertmann-Sträussler-Scheinker Syndrome (GSS) Determined by an Autosomal Dominant Mutation in the Prion Protein Gene (PRNP)

A, Pedigree showing that the maternal partner is a 27-year-old asymptomatic woman with an F198S mutation identified by predictive testing in a family with a known history of GSS due to an F198S mutation in the PRNP gene (phenylalanine to serine substitution at codon 198). Marker order in relation to the gene is shown on the left. B, Sequential PB1 and PB2 mutation analysis in 12 oocytes, with the results available for 9 oocytes, 4 of which had the mutation, including 1 recombinant oocyte (oocyte 13). The remaining 5 oocytes with DNA results were free of the F198S mutation (oocytes 2, 3, 7, 10, and 14), 3 of which were from oocytes with heterozygous PB1 and hemizygous mutant PB2 (oocytes 7, 10, and 14). C. Blastomere analysis of 8 embryos deriving either from the oocytes with failed amplification of PB1, ADO of linked markers, or from affected oocytes for confirmation. This analysis allowed detecting 1 additional mutation-free embryo for transfer (embryo 1), deriving from a mutation-free oocyte and confirmed normal. Two healthy embryos were transferred, resulting in the birth of healthy twins with a very high likelihood (91%-98%) of being free of the F198S mutation, likely without predisposition to this familial fatal prion-related neurodegenerative disorder. ADO, allele dropout, refers to the inability to detect an allele during polymerase chain reaction (PCR) through amplification of linked markers; FA, failed amplification, the inability to amplify the gene of interest via PCR; PB1, the first polar body, extruded from the mature oocyte and the outcome of meiosis I, containing 2 copies of maternal DNA; PB2, the second polar body, extruded following fertilization of the oocyte and the outcome of meiosis II, containing 1 copy of maternal DNA.

Elective single embryo transfer to prevent multiple pregnancy was discussed, and the patient elected to transfer 2 embryos. Based on PGD analysis, 2 mutation-free embryos (Nos. 1 and 3) (Figure) were chosen for fresh embryo transfer, with 3 remaining viable embryos designated for cryopreservation.

Quiz Ref IDThe 2 embryos implanted successfully, and the patient conceived twins. Healthy infants were delivered by a Cesarean section at 33 weeks and 5 days of gestation, each weighing more than 4 pounds. As expected, due to their prematurity, the infants were slightly below the curve for weight for age and for head circumference, both of which normalized by age 3 months. By age 27 months, the infants had consistently completed communicative, social, and emotional developmental milestones on schedule.


To our knowledge this is the first published report of IVF with PGD for a genetic prion disease with 27-month normal follow-up of the offspring. Although the patient in our case chose to learn her genetic status, because of emotional risks associated with learning one’s carrier status of a PRNP gene mutation, nondisclosure PGD (a specialized protocol in which the subject remains unaware of his/her genotype) was discussed as an option.2

Other forms of genetic prion disease and other inherited neurologic disorders are also candidates for PGD.5,6 For example, guidelines from professional reproductive societies have been created for PGD in Huntington disease,5 and similar guidelines for other neurologic conditions may be forthcoming.

Quiz Ref IDIn summary, PGD can serve as a viable reproductive option for patients faced with genetic prion disorders, such as GSS, and may affect their inclinations for predictive testing and consideration of nondisclosure PGD. Clinicians should discuss PGD as an option with patients genetically predisposed to prion disease.

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Article Information

Corresponding Authors: Ilan Tur-Kaspa, MD, Institute for Human Reproduction, 409 W Huron St, Ste 500, Chicago, IL 60654 (, or Murali Doraiswamy, MBBS, FRCP, Neurocognitive Disorders Program, Department of Psychiatry and Duke Institute for Brain Sciences, DUMC 3018, Durham, NC 27710 (

Accepted for Publication: November 13, 2013.

Published Online: February 3, 2014. doi:10.1001/jamaneurol.2013.5884.

Author Contributions: Dr Tur-Kaspa had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Uflacker, Doraiswamy, Rechitsky, Geschwind, Tur-Kaspa.

Acquisition of data: Rechitsky, See, Geschwind, Tur-Kaspa.

Analysis and interpretation of data: Uflacker, Doraiswamy, Rechitsky, Geschwind, Tur-Kaspa.

Drafting of the manuscript: Uflacker, Doraiswamy, Tur-Kaspa.

Critical revision of the manuscript for important intellectual content: Uflacker, Doraiswamy, Rechitsky, See, Geschwind, Tur-Kaspa.

Obtained funding: Doraiswamy, Rechitsky, Geschwind, Tur-Kaspa.

Administrative, technical, and material support: Doraiswamy, Geschwind.

Study supervision: Doraiswamy, Rechitsky, Geschwind, Tur-Kaspa.

Conflict of Interest Disclosures: Dr Doraiswamy has received research grants (through Duke University) from Elan, Avid, Lilly, Novartis, Neuronetrix, Medivation, Wyeth, Janssen, Pfizer, and National Institutes of Health (NIH) over the past 3 years. He has received advisory or speaking fees in the past from Accera, Avid, AstraZeneca, Abbvie, Baxter, Cognoptix, Lundbeck, Takeda, Piramal, Genomind, Sonexa, Shire, Targacept, Grifols, Neuronetrix, TauRx, Medivation, Danone, Neurocog Trials, Alzheimer’s Association, Alzheimer’s Foundation, University of California, National University of Singapore, and University of Copenhagen. He owns shares in Maxwell Health, Sonexa, Clarimedix, and Adverse Events Inc, whose products are not discussed here. Dr Rechitsky is employed by the Reproductive Genetic Institute, where the PGD procedure was performed. Dr Tur-Kaspa is employed by the Institute for Human Reproduction, where the IVF was performed. No other disclosures were reported.

Funding/Support: Drs Uflacker and Doraiswamy did not receive any specific external support for this work. Drs Rechitsky and Tur-Kaspa were supported by the Reproductive Genetics Institute and the Institute for Human Reproduction, Chicago, Illinois, respectively. Dr Geschwind was supported in part by National Institute on Aging/National Institutes of Health (NIH) grants R01 AG031189 and P50 AG023501; NIH/National Center for Research Resources, University of California San Francisco Clinical and Translational Science Institute grant UL1 RR024131; The Michael J. Homer Family Fund; and Alzheimer’s Disease Research Center of California grant 10-10030.

Role of the Sponsor: The supporting institutions had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We are grateful to our patient for allowing her case to be presented in this publication.

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