EyeNet Magazine

Clinical Update: Genetics
Screening for Stargardt: Choices Before Pregnancy
By Miriam Karmel, Contributing Writer
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This is a story about a baby whose arrival required a lot more than birds and bees. Only through the concerted efforts of a mom- and dad-to-be, their ophthalmologist, geneticists, and assisted-fertilization specialists, was a healthy girl born into a life unclouded by Stargardt disease.

“When younger couples affected by Stargardt come in, they almost always ask about the chances of passing on the disease,” said R. Theodore Smith, MD, PhD, professor of ophthalmology and biomedical engineering at Columbia University. “We used to say it’s a rare disorder and chances are low, so go about your merry way. But the paradigm has shifted. We can’t say that now, when there is a chance to tell them about other options.”

Those options were outlined recently in a case report involving the girl born with healthy eyes. The baby’s father was a patient of Dr. Smith’s, and his story documents the first use of in vitro fertilization (IVF) and preimplantation genetic diagnosis (PGD) for Stargardt disease.1


A Look at Methodology

Stargardt is a classic recessively inherited disease requiring one allelic mutation from each parent for offspring to be affected. While Stargardt mutations are not considered common, neither are they rare, said Dr. Smith. The patient possessed two Stargardt alleles, so if the patient’s wife turned out to be a carrier, “their chances of delivering a baby with Stargardt would go from very, very low up to 50 percent,” Dr. Smith said. Following genetic counseling, testing confirmed that the father possessed two mutations of the gene associated with Stargardt—ABCA4. His wife possessed one mutation.

ABCA4 is the photoreceptor-specific gene whose variants have also been associated with retinitis pigmentosa and some cone-rod dystrophies. ABCA4 is a very large gene, and for Stargardt alone over 500 mutations of the gene have been identified. “The severity of the disease depends on which two mutations you inherit,” said Richard A. Lewis, MD, MS, who in 1985 conducted work to identify genes for hereditary eye disease and was among the first to map the gene for Stargardt disease. Dr. Lewis is now professor of ophthalmology and molecular and human genetics at Baylor College of Medicine in Houston.

Taking control of matters. Knowing each of their children had a 50 percent chance of developing Stargardt disease, Dr. Smith’s patient and his spouse decided to pursue a pregnancy through IVF and PGD. Controlled ovarian stimulation yielded 17 oocytes, 16 of which were successfully fertilized with the husband’s sperm. Six possessed mutant alleles from each parent, and thus were predicted to develop Stargardt disease. Three were inconclusive and six had a normal, healthy maternal allele of the gene. Of those six, one embryo was implanted.

During the first trimester, chorionic villus sampling was performed to confirm that the embryo indeed possessed a normal maternal allele.


New Options, New Question

The parents got what all parents would want: a child unaffected by a blinding disease. And the researchers demonstrated that it could be done—at least for Stargardt disease. “I think it’s going to be a model for other inherited recessive diseases in which the gene is known,” Dr. Smith said. But, he added, the genetic knowledge for other eye diseases is so incomplete that it would be premature to try to replicate the Stargardt success for patients, say, with retinitis pigmentosa, which comprises a huge range of diseases.

Mahsa A. Sohrab, MD, who coordinated the Stargardt preimplantation project at Columbia, agreed. Cone-rod dystrophies have so many phenotypes and involve so many different genes and mutations that “even screening for the mutations we know could leave you missing something,” she said. “A lot of these diseases have complicated genetic profiles, so that’s why it hasn’t caught on like wildfire. Even in this case, we made it clear in the consent process that we cannot promise, even if the preimplantation biopsy of the embryo is clear, the child is not going to have the disease. That’s why we did the chorionic villus.”

In spite of the caveats, a disease like Stargardt, which is 100 percent genetic and for which the single gene is well known, lends itself well to the option of preimplantation genetic diagnosis. “For the genes that are known,” said Dr. Smith, “we can intervene in this way for parents who are anxious about their next child.”

The desire to raise healthy children is understandable, but does it justify an intervention that can raise ethical, clinical and economic considerations?

The money. For starters, insurance doesn’t cover the use of IVF and PGD, which costs anywhere from $15,000 to $20,000 per effort, said Dr. Sohrab.2 “A limitation of our study is that only certain people, those who can afford it, can use this technique,” she said.

The medicine. The procedure is not completely benign. Potentially, the needle used in chorionic villus sampling could damage the amniotic sac or injure the fetus, Dr. Sohrab said.

The morals. All but three of the embryos created during IVF were discarded, an inevitability of this technology that some people oppose on ethical grounds. Interestingly though, Dr. Sohrab found that a lot of couples choose PGD precisely because they believe it is a way for them to avoid the contingency of aborting a fetus.

Even so, PGD raises a “slippery slope” argument. “Some people might be concerned that the use of PGD to avoid Stargardt disease—which, though debilitating, is not life-threatening—could lead to its use for selection against more benign conditions,” said Dr. Sohrab. But she does not subscribe to this argument, which likens relatively trivial problems to a profound one like Stargardt. “I have worked with children with Stargardt disease and know that they face many daily life challenges, as do their parents.”


Tied Up in Knots

“We now have so much knowledge available about the genetics of retinal degeneration that people should be aware of it,” Dr. Smith said. But the challenge to ophthalmologists will be keeping up with the pace of such rapidly unfolding knowledge. “This is going to take at least another generation of physicians who, in medical school, get education as to what tests are valid and what information to provide to genetic counselors.”

Dr. Lewis chairs the steering committee for eyeGene, the NEI-supported National Ophthalmic Disease Genotyping Network (www.nei.nih.gov/resources/eyegene.asp). Its goals include facilitating research on the genetic causes of ocular diseases, providing genotyping for patients with inherited eye disease and creating awareness of resources for patients and physicians. A physician who suspects a patient might have an inherited disease can send a blood sample to the NEI for DNA analysis. Part of that sample will go into a national repository for future research. The eyeGene website lists all the genes and diseases being tested by the network. Other sources of information include the National Society of Genetic Counselors at www.nsgc.org and the American Society of Human Genetics at www.ashg.org.


Physicians, Patients, Prerogatives

Dr. Lewis said he preferred leaving moral judgment calls to patients. “It’s a question of what you do with this information,” he said. “If you could advise couples that their risk is 25 or 50 percent, that couple could choose to use that information in a fashion that is consistent with their personal, ethical, moral and religious beliefs. My job is not to tell them what to do. My job is to give them the information to allow them to make informed choices. My responsibility as a physician is to be the safety monitor at the school crossing. I have to tell you what the traffic looks like at left and right. And an ophthalmologist can tell you what life is like with the burden of this or any other visually debilitating disease.”

When info about a gene offers choices. Once a gene for a disease is isolated and its complete genetic structure is understood, a couple wanting to have children has at least three options, Dr. Lewis said. One, take their chances having a child with the disorder. Two, fix the disease through gene therapy, as has been reported recently in the treatment of one genetic form of Leber congenital amaurosis.3 Or three, block the genetic continuation of the disease, as Dr. Smith’s patient did. A similar preventive effort occurred following the discovery of the gene for Tay-Sachs, a deadly degenerative neurologic disease. A huge educational campaign was launched to raise awareness about Tay-Sachs and encourage carriers to seek genetic counseling.

“We’re in the middle of a long journey,” Dr. Lewis said. “The ultimate goal is to reduce the burden of hereditary eye disease in the population.”

1 Sohrab, M. A. et al. Am J Ophthalmol 2010;149(4):651–655.
2 Robertson, J. A. et al. Hastings Cent Rep 2002;32(3):34–40.
3 www.nei.nih.gov/lca


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