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Case Report/Case Series |

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

Alice Uflacker, MD1; P. Murali Doraiswamy, MBBS, FRCP1; Svetlana Rechitsky, PhD2; Tricia See, CGC3,4; Michael Geschwind, MD3; Ilan Tur-Kaspa, MD2,5,6
[+] 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.
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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.

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Figure.
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.

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