Genetic Diagnosis Before IVF Avoids Prion Disease

Pauline Anderson

February 04, 2014

A technique called preimplantation genetic diagnosis (PGD) has allowed a woman carrying the gene for Gerstmann-Sträussler-Sheinker syndrome (GSS), a fatal neurodegenerative disorder linked to abnormal prion protein folding, to selectively implant only embryos free of the mutation and give birth to healthy twins.

Neurologists should be aware of this reproductive medicine technique that can identify genetic defects leading to neurologic disorders in embryos created through in vitro fertilization (IVF) before implantation, the researchers on this new case report, led by Ilan Tur-Kaspa, MD, founder and medical director, Institute for Human Reproduction, and clinical professor, Department of Obstetrics and Gynecology, University of Chicago, Illinois, conclude.

Until recently, such prospective parents had few choices beyond adoption, using donor eggs, or remaining childless. Dr. Tur-Kaspa calls PGD "a form of a modern preventive medicine."

He is senior author of what he believes is the first published report of IVF with PGD for 1 of the genetic prion diseases, also called transmissible spongiform encephalopathies. The case report is published online February 3 in JAMA Neurology.

To date, PGD has been performed successfully for many early- and late-onset neurologic and neuromuscular diseases, Dr. Tur-Kaspa told Medscape Medical News. These include autosomal recessive disorders, such as spinal muscular atrophy, ataxia-telangiectasia, Canavan disease, Tay-Sachs disease, Gaucher disease types 2 and 3, and Sandhoff disease; autosomal dominant disorders, such as amyotrophic lateral sclerosis, Huntington disease, Charcot-Marie-Tooth disease, familial Alzheimer disease; and X-linked disorders, including fragile X syndrome and Duchene muscular dystrophy.

Mutation Carrier

The current case involved a 27-year-old woman with a known family history of GSS syndrome, with both her father and other relatives being affected by about age 50 years, said Dr. Tur-Kaspa.

The woman had decided to undergo predictive testing after receiving genetic counselling and was identified as carrying the F198S mutation of GSS. She had opted to be informed of the genetic test results "to allow her to plan her life," Dr. Tur-Kaspa, and she and her husband decided to pursue PGD.

During IVF, doctors retrieved 14 mature oocytes, 12 of which were fertilized. Six of these embryos were mutation free, and 2 were transferred into the woman's uterus. Three of the remaining embryos were cryopreserved.

The woman went on to deliver 2 babies — a boy and a girl — via cesarean section at 33 weeks and 5 days gestation, each weighing more than 4 pounds. By age 27 months, the children were completing various developmental milestones on schedule.

Since then, Dr. Tur-Kaspa said, the woman has had another 1 of the cryopreserved embryos implanted and has delivered another healthy baby.

Ethical Issues

Dr. Tur-Kaspa doesn't see ethical issues standing in the way of PGD. He said that the American Society for Reproductive Medicine has confirmed that PGD for late-onset disorders that lead to "chronic debilitating and fatal disorders," such as the one outlined in the case report, is ethical.

Reproductive medicine is constantly changing and with it society's acceptance of it. Dr. Tur-Kaspa pointed out that when IVF was first introduced back in 1978, some people equated it with "creating monsters in test tubes."

But today's practitioners may not be aware of the PGD option, he said. Upwards of 90% of internists responding to a 2012 survey reported that they had never suggested PGD to a patient and most felt unqualified to answer PGD-related questions, said Dr. Tur-Kaspa. He added that neurologists may be equally reluctant to discuss the topic.

Dr. Tur-Kaspa wants neurologists to be up to date on IVF and PGD achievements. "The idea is to let them know that this is a very successful procedure, that young patients can expect an excellent outcome, that there have been thousands of babies born after PGD, and it seems to be safe," he told Medscape Medical News.

Neurologists who have patients with a genetic disorder who are planning a family should recommend that these patients see a genetic counsellor or talk to a reproductive specialist, said Dr. Tur-Kaspa. However, he stressed that it's the patients themselves, and not neurologists, who should be making the decision regarding PGD.

"Neurologists don't have to be involved in the decision; they should just know about this."

2-Edged Sword

In an accompanying editorial, Golder N. Wilson, MD, PhD, Texas Tech University Health Science Centers, Amarillo, called PGD "a 2-edged sword."

Its benefits of comprehensive screening by microarray analysis and rapid "NextGen" sequencing "are tempered by high costs, unequal access, and the uncertain consequences of nucleotide change," said Dr. Wilson.

Among the ethical issues surrounding PGD are the "usual societal and religious objections to artificial reproductive technology and abortion," as well as the issue of access to care, with PGD costing $10,000 to $20,000, according to Dr. Wilson.

A specific concern for neurologists, he writes, is PGD for disorders presenting later in life, such as Huntington disease. He stressed that focusing on 1 gene or disease outcome may not prevent others.

Neurologists may be the "NextGeneticists" who, by being "uniquely familiar with molecules and magnetic resonance images," will be necessary to "peruse, predict, and astutely prevent the multifaceted sequences of neurological disease," concluded Dr. Wilson.

Support for the study came to individual coauthors from the Reproductive Genetics Institute and the Institute for Human Reproduction, Chicago, Illinois; the National Institute on Aging/National Institutes of Health (NIH); NIH/National Center for Research Resources, University of California San Francisco Clinical and Translational Science Institute; The Michael J. Homer Family Fund; and the Alzheimer's Disease Research Center of California. Dr. Tur-Kaspa is employed by the Institute for Human Reproduction, where the IVF was performed. Dr. Wilson has disclosed no relevant financial relationships.

JAMA Neurol. Published online February 3, 2014. Abstract Editorial

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