17 Oct 2014

Would-be parents from families carrying devastating genetic mutations face a formidable decision: Should they have children and risk passing on the disease? It is even more complicated when the at-risk parent doesn’t know his or her genetic status, and wants to keep it that way. There is a procedure that enables them to circumvent these concerns. At the 139th annual meeting of the American Neurological Association, held October 12-14 in Baltimore, Murali Doraiswamy of Duke University, Durham, North Carolina, described the first such case from a family carrying a presenilin 1 (PS1) mutation. The woman, who chose to remain anonymous, now has 2-year old twins who have almost zero chance of carrying a familial AD mutation.

For the past two decades, doctors have used a combination of in vitro fertilization and preimplantation genetic diagnosis (PGD) to implant only embryos they know to have escaped the particular family mutation. Doctors can perform the procedure without revealing whether the parent carries the harmful gene (see Jul 2014 news story). However, even after 20 years, PGD remains relatively unknown, especially among families carrying alleles for familial Alzheimer’s disease (FAD). Not even a dozen couples from such families have used the procedure to conceive, in part because few know about it (see Jul 2014 news story). 

While this 30-year-old woman wanted to spare her children the prospect of early onset Alzheimer’s, she did not want to know if she carried the mutant PS1 herself. To conceal her status, a team headed by Svetlana Rechitsky of Reproductive Genetics Institute, Northbrook, Illinois, performed what’s called indirect linkage analysis on cells from nine embryos conceived by in vitro fertilization. This was to ensure the woman passed on a normal copy of the PS1 gene, inherited from her father, rather than a mutant copy, which would have come from her mother, who had a confirmed diagnosis of AD. Rechitsky and colleagues conducted genetic testing on the couple and their parents to identify genetic markers that lay near PS1. Then they screened the embryos to identify those that contained the unaffected grandfather's copy of the gene, then implanted only those embryos. The point of this process is that the researchers never looked for the mutant PS1 allele itself. If a chromosome had markers around PS1 from the woman’s affected mother, that embryo was considered “at risk” of containing the mutated PS1 allele, and was not implanted.

PGD is not widely recognized as a potential solution for families who carry early onset AD mutations. Some of the few couples who have undergone PGD for FAD know about it from their own professional experience as doctors, geneticists, or neuroscientists, or they found out about it while seeking in vitro fertilization for other reasons, Doraiswamy told Alzforum. Some who learned about it in later years say they would have considered it before having children, but only a trickle of FAD cases comes through the door, said Doraiswamy. “Doctors and patients need to be educated,” he said.

Another problem is that few insurance companies in the United States, and only some in other countries, cover in vitro fertilization for fertile couples, while PGD is not covered for any conditions in the United States, according to Doraiswamy. The expense for combined PGD and in vitro fertilizations, which can run to $30,000 or more, deters couples, he said. On the other hand, a young woman from a different family who is similarly at risk of FAD but was not connected to this case told Alzforum, on condition of anonymity, that even if her insurance did cover PGD, she would not trust that her information would be kept confidential. So long as cost and genetic privacy remain obstacles, PGD may well remain a high-tech option for the affluent few.—Gwyneth Dickey Zakaib