The Indianapolis Experience: Five years after Lannfelt's report, an extraordinary set of papers on predictive testing for eFAD appeared in the Journal of Genetic Counseling. Kimberly Quaid, a research clinician in genetic testing, and colleagues including Martin Farlow and Bernardino Ghetti, the head of the Indiana University Alzheimer Disease Research Center (ADRC), narrated their perspective on testing a family alongside a first-person account by a mutation carrier in that family. The package highlighted the tension that can ensue when a provider's cautious protocol gets pitted against the complexities of family dynamics on the one hand and against the demands of informed, impatient family members on the other.
The story began when a 42-year-old woman was referred to the Indiana University Alzheimer Disease Research Center with a history of memory loss and disorganized behavior. Her father had shown signs of dementia before dying young from a heart attack, and a younger sibling had cognitive deficits, too. Genotyping of the woman's blood identified a new mutation in the APP gene, and made predictive testing for her five siblings possible.
The family was invited to meet the ADRC clinical staff; two thirds attended. The researchers laid out the siblings' options: do nothing, participate in clinical research with the separate option of learning their results, and/or learn their genetic risk. Grant funds were available to cover travel and lodging expenses for research participation and for part, but not all, of the predictive testing regime. This became a source of tension later on. At this initial meeting, one sibling stated that all would want to participate to the full extent offered, including predictive testing. The same sibling called back to confirm that all siblings wanted this. In the course of the process, however, cracks among the siblings emerged.
First, one turned out to already show signs of cognitive impairment in spite of the siblings' denial, and for this person the genetics would confirm a clinical diagnosis. The clinicians found themselves in the position of having to diagnose this person appropriately and privately with only the spouse present, while at the same time keeping all the other siblings within the predictive testing protocol, and the negotiations around this were fraught with tension. Second, another sibling later decided that (s)he did not wish to learn his/her genetic status at all, or even be followed regularly. (S)he needed to fend off family pressure to get tested as a group.
Communications between the center staff and the sibling who acted as a spokesperson and made joint decisions, as well as the other siblings, were strained at times. One sibling's tendency to view all siblings as a group conflicted with the clinician's approach of treating each as an individual, preferably as a unit with his/her respective spouse. Several siblings saw AD as a family problem and wanted to take the required steps together. Yet each was married, at a different stage of their lives, and they eventually came to see that they needed to include their spouse in the counseling, and receive the test result with only the spouse in the room.
Moreover, some of the siblings balked at the genetic counseling protocol the center insisted on following. They felt they knew enough to "just find out." They objected to being cajoled into a process that required repeated air travel at their own expense. They felt patronized. For their part, the clinical staff held firm on their professional responsibility to protect the siblings from unforeseen implications of knowing their genetic status, particularly since the siblings were pioneering a new era in genetic medicine. Predictive testing in AD was still so rare. It was the first time this ADRC performed it and they wanted to do it right. Negotiations about cost, individual exceptions, and special arrangements ensued. When the director of the genetic testing program sent a detailed letter to every sibling, laying out core requirements and the reasoning behind it, both sides eventually found a compromise. One sibling underwent counseling at a qualified center near his/her current home, and flew to Indiana to receive the test result.
One of the three carried the mutation. News of the result met "tearful stoicism" and "stunned silence" on the part of the sibling and the spouse, according to the report. The siblings called and e-mailed with follow-up questions but did not take advantage of the center's offer to schedule further sessions. One year later, they returned for follow-up. The sibling who has AD had progressed mildly, the sibling who had rejected testing still did, and the sibling who turned out positive was pursuing pre-implantation genetic diagnosis in order to have a child who would not carry the mutation. The family remains interested in research participation and came through this crisis intact, indeed closer.
The path toward this positive overall outcome was draining for all, the authors note, and they offer some lessons for others in the same situation. Direct communication between center staff and each individual family member all along the process is critically important to prevent misunderstandings among siblings and to establish the authority of the clinical director. The underlying challenge of balancing the patient's autonomy with good clinical practice runs through the literature on genetic testing for other diseases, as well. Patients feel entitled to "their" information, and the provider insists on providing it in an appropriate way. Open discussion allows the patient and the provider to reach a mutual understanding. Personal follow-up calls from the provider to each affected family member, just to check in on how each is doing, can further improve relations with the patients and build an ongoing clinical relationship (from Quaid et al., 2000, J. Genetic Counseling, Vol.9).
The Seattle Experience: By 2001, enough people had chosen predictive eFAD testing and agreed to continue with research that it became possible to advance from anecdotal, single-family reports to studying a group and distilling some general information. The first such study came from the group of Thomas Bird, the neurogeneticist at the University of Washington in Seattle. Bird has studied Huntington disease—considered a model for eFAD—in addition to Alzheimer disease and similar disorders that fall into a group called frontotemporal dementias. The Seattle clinicians followed presymptomatic carriers for up to 3 years to see how knowing had affected them psychologically, how it had shaped their lives, and whether they regretted having taken the test. The clinicians shared their data with the research community in a report in the journal Archives of Neurology. Their overall impression was one of cautious optimism that DNA testing could be worth it, but important caveats turned up as well.
The study included at-risk descendants from families with eFAD and a related disorder called FTDP-17. Of 251 candidates for testing (meaning each had an affected parent and 50 percent risk), 58 people first expressed interest and 21 eventually opted to go through with it. Sixteen of those were at risk for eFAD, five for FTDP-17, and six of them proved to already be in early stages of disease. These six and their families considered the DNA test helpful in clarifying the situation and helping them plan their lives.
Fourteen asymptomatic people were in their thirties and forties. Two had the test done but postponed hearing the results for 2 years. Six were positive for their respective family's mutation. One refused all further contact and the researchers do not know how (s)he is faring. Most others, when asked afterwards if they would recommend DNA testing, said they would leave it up to the individual, but none said they would advise against it. People with positive results were disappointed, but tended to say they were glad to know and to have clearer choices for planning their future. As expected, non-carriers were grateful and relieved. Unexpectedly, however, the follow-up visits and exams showed that some of them continued to wrestle psychologically with AD. Some worried about it all the time even years after the test. Perhaps this should surprise no one as the disease, after all, continued to burden their lives and claim living relatives. The DNA test itself did not cause depression. One person who was depressed had been depressed before the test and turned out to be negative for the disease. The test did not relieve depression, either. Four people scored high on a measure of avoidance, that is, they protected themselves by trying not to let AD enter their minds. Two of them were positive; two others had postponed hearing their results. There were no psychiatric hospitalizations or suicide attempts.
Curiously, some people have strong feelings about how their test will turn out. One person, upon finding (s)he was positive, said the result "confirmed what I thought." Another had gone through counseling and the blood draw but then felt ambivalent and at the last minute delayed hearing the result to prepare emotionally. Then, when the result proved negative, (s)he said, "I was so convinced I carried the abnormal gene that I have to retrain my mind to think differently…. Now I have a future."
With regard to concerns about social discrimination, the researchers to date have not heard of a person with a positive result having lost employment or been denied insurance, though this concern is certainly real. The test clearly ripples through personal lives, but not in any particular way. One presymptomatic carrier went through marital separation, one non-carrier went through with a divorce and another with a second marriage; all three said the test influenced their decisions. Likewise, family planning changed but not in any one direction. After finding out, one carrier decided against a second pregnancy but another carrier had a first child. A third person had a first child during the self-imposed hiatus between blood draw and finding out (from Steinbart et al., 2001 and personal interview).
This is still a small study, and more data are needed before one can generalize more broadly. Moreover, true long-term follow-up data are still not in. What happens 5 years out? Ten years later? Do people who know their genetics react differently as the first disturbing symptoms appear?
The Barcelona Experience: Recently, Spanish researchers have reported similar results with a smaller group of nine at-risk relatives from families in the Catalan capital of Barcelona. Ranging in age from their twenties to their forties, they came from a family with eFAD, a family with a frontotemporal dementia, and a family stricken with a rare fatal insomnia that is caused by a mutation in the same gene that is also associated with Creutzfeldt-Jakob disease and the cattle disease BSE. (While these diseases are different, they are incurable and raise nearly identical issues of genetic testing.) The relatives chose predictive testing because they wanted to use early treatment in the future. They also cited the anxiety of not knowing their future, the need to plan their families, and the wish to tell their children.
Five descendants from the family with eFAD chose testing. Two who turned out not to carry the mutation were relieved, though one doubted the test: "I had always been sure that I had the mutation." One decided to have another child. Two relatives had the mutation, and for a fifth the positive test became part of the diagnosis because (s)he was already symptomatic for AD at 38. The two carriers showed sorrow when they heard of their results. One developed intense anxiety in the next few weeks but returned to normal in the post-test follow-up program. (S)he worked less, spent more time with family and hobbies, and decided to tell the children when symptoms would begin. The other carrier had come to the study with high anxiety, which abated when (s)he found out. (S)he stayed emotionally stable, made no major lifestyle changes, and said that relief of a nagging uncertainty was the biggest benefit. Both carriers decided to have no more children and regularly visit a neurologist for follow-up. The relative from the frontotemporal dementia family took a similar course. Upon learning (s)he carries the gene, previously high anxiety eased and (s)he regularly visits a psychiatrist as part of the follow-up. The descendants of the third family all escaped the mutation. Two said they had expected "the worst." None of the non-carriers developed survivor's guilt.
Unlike U.S. families, the Spanish families did not cite concerns about insurance, largely because Spain has universal national health care, as do other countries in the European Union. The Spanish cited no concerns about employment discrimination, nor did the carriers make significant changes in these areas. There were also no changes in their marriages. The Barcelona study found no depression as a consequence of DNA testing.
Like most academic investigators in this area, the Spanish scientists used an extensive counseling protocol modeled on HD and emphasize that predictive testing should always be embedded in careful pre-test education and post-test follow-up. Their pre-test program called for the clinical staff (neurologist, psychologist, psychiatrist) to discuss every case and, based on their assessment of the person's ability to cope with a positive result, recommend that the person proceed or not. However, even in cases where the professionals felt the psychological damage might outweigh benefits, they did not deny that person the right to know if (s)he insisted. The patient's autonomy trumped the provider's caution. The Barcelona participants valued the testing program for providing sought-after information, relieving uncertainty, and offering long-term care after the test (Molinuevo et al., 2005).
In summary, both the Seattle and Barcelona clinicians stated that predictive testing for eFAD can be done safely. They noted, however, that their participants were a self-selected group of people who insisted on having access to genetic testing. This drive to self-determination might be a good indicator for a person's ability to deal with the results in the aftermath. In other words, much as this determination should be honored, others who feel ambivalent about predictive testing must never be pressured into it. On balance, then, the literature available to date tends to agree that DNA testing for eFAD and FTD can be valuable provided it happens in the appropriate context. The risks are real and not fully understood yet.
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