By Gabrielle Strobel
Jennifer Williamson is a genetic counselor at the Taub Institute for Research on Alzheimer's Disease and the Aging Brain and the Gertrude H. Sergievsky Center at Columbia University, New York. She sees families with neurogenetic disorders for which testing is available but that have no cure. Her article, with Susan LaRusse, "Genetics and genetic counseling: recommendations for Alzheimer's disease, frontotemporal dementia, and Creutzfeldt-Jakob disease," is widely read among her colleagues (Williamson and LaRusse, 2004). The paper describes different types of available genetic testing, and discusses the counseling challenges involved in helping patients and healthy relatives make informed and autonomous decisions. For more detail on the issues raised in this conversation, see the essay Early Onset Familial AD: Genetic Testing and Counseling. See also Protocol for Predictive Testing.
Williamson: People with EOAD are left at sea with their overwhelming problems, with few resources available. I see that in my practice. At most Alzheimer Association meetings I have gone to here in New York City, there is always one person who has a family member with EOAD, and this person often feels that he or she does not quite fit in with the support group. The person's issues are not the same because he or she is dealing with someone who is much younger, has young children, and faces different problems at home and with the care. Then there are the genetics issues. Families with frontotemporal dementia are similarly left out.
ARF: How often do you see people with eFAD?
Williamson: I rely on the physicians in our Alzheimer Disease Research Center (ADRC) to let me know when they have a family that could benefit from genetic counseling. I see about a dozen a year.
ARF: Why is it important to have genetic counseling in this situation?
Williamson: If genetic testing is on the table, the implications are not only for the patient but for the siblings and the children. The patients and their primary support person, usually the spouse or a sibling, both need to be informed of what the implications are of having such a diagnosis before genetic testing occurs.
ARF: What protocol are you using?
Williamson: We follow the model for Huntington's disease genetic testing (see sample protocol). For symptomatic people, it requires that they first have a clinical diagnosis by a neurologist. Then it requires multiple genetic counseling sessions with a genetic counselor and neurologist prior to testing, and potentially a meeting with a psychiatrist or our social worker here at the ADRC. For presymptomatic testing, for example if we have a symptomatic patient with a PS1 mutation and he or she has a sibling who wants testing, we require that they follow a set protocol of genetic counseling, a visit with a psychiatrist, a neurological and neuropsychological evaluation, blood draw, etc. I do predictive testing for HD more frequently than for AD. In my experience, many of the eFAD families are willing to participate in research but they do not necessarily want to know their own genetic status.
ARF: Is there a consensus protocol that genetic counselors tend to adhere to, or is every center following its own?
Williamson: A bit of both. Centers lean on the HD protocol, and then in their own daily practice do things a little differently depending on what resources they have available to them. There are no formal guidelines that all ADRCs adhere to, and the National Society of Genetic Counselors has not formulated any, either. But the literature contains many papers with recommendations for genetic testing. Some are consensus statements on ApoE in LOAD, and these statements talk about testing for eFAD, as well. They tend to follow the HD model and all of them refer to the need for genetic counseling.
ARF: Is there universal consensus on the need for genetic counseling for neurogenetic testing?
Williamson: In my experience, clinical geneticists support the need for genetic counseling by genetic counselors more than neurologists. Some neurologists use counselors, others run a case by a counselor for advice but then do not use a counselor in their further care of the patient, and yet others do not consider counseling before ordering the test for a patient. Whoever does the counseling, it is important to make sure that a patient is well aware of what it means to have a genetic diagnosis in the family. It would be good for families to know that genetic testing can be done in a careful way.
ARF: Do families really want counseling?
Williamson: Some initially resist the idea of multiple counseling sessions. They simply want to know the result of this blood test. But believe me: after going through the process, they really benefit from it. Counselors are in tune to the issues that arise.
ARF: What are the issues?
Williamson: For example, whom do you tell? When you find out that your 45-year-old spouse has EOAD and it is genetically confirmed and your children are at 50 percent risk, how do you tell your children? When do you tell them? I don't know that every physician necessarily covers these issues, but the genetic counselor does. We talk with people beforehand about these things rather than after. Our experience is that a multidisciplinary approach is ideal.
ARF: Nice advice if you can get it?
Williamson: Yes, access is a problem, considering that most people do not live near an academic medical center. ADRCs may offer this because they have the resources. They have psychiatrists and social workers on staff, and if they do not have a genetic counselor they could call on one from a clinical genetics group.
ARF: Not even all ADRCs have genetic counselors?
Williamson: No. Remember that eFAD testing is not yet frequently done. We see EOAD all the time, but true autosomal-dominant families for whom testing is necessary are rare. Cost is another reason holding down use. Many insurance companies do not pay for this test.
ARF: Do you have a research study that covers genetic testing?
Williamson: No. Most of our research is for LOAD and does not cover clinical genetic testing. At our center, we keep a clear line between research and clinical care. Other groups have a less clear line and have protocols that allow for clinical testing paid through a grant. Clinically, Athena Diagnostics offers presenilin 1 testing, not APP or PS2.
ARF: How expensive is the PS1 test?
Williamson: Close to $1,000.
ARF: Say a person already has symptoms and then gets a positive result. What will happen?
Williamson: We disclose the result. We do a minimum of a follow-up call. Our staff neurologists continue to follow the patients. Genetic counseling then becomes available to their adult siblings. Usually their issue is "What about my kids?" Clearly, genetic testing for young children is not appropriate in this situation. The counseling deals with having a conversation with your children at the right time about having this disease in the family.
ARF: What do you recommend?
Williamson: I have trained with one of our social workers in HD, who adapted her experience with adoption to talk about genetic disease. You introduce the idea of what the disease is as early as possible but avoid labeling it at first as genetic. It is best to talk honestly with children as they ask questions, that is, "Is this what Aunt Mabel has, too?" "Yes." We inform about how to talk honestly without bringing up additional information that they are not asking about. If children ask a question, think about what they really are asking about and answer that but never say anything that is dishonest. Communicate so they can gradually absorb it as they mature but are not overwhelmed at any point.
ARF: How about telling adult siblings?
Williamson: I advise that they need to tell them. And that their siblings may or may not want to get tested. They should neither encourage nor discourage testing, or expect their siblings to do as they did. They should let their siblings know of the resource of genetic counseling, and how to contact me should they want to learn more.
ARF: How about extended branches of the family? Say someone has a diagnosis and confirmed mutation, and an uncle had the disease too and left descendents. Should the patient tell these cousins?
Williamson: I leave that up to the family. It depends on their relationship. It's good to let them know but not urge them to get tested. People do not like to be told what to do.
ARF: Do you stay in touch and hear back, or do you lose sight of families once the immediate protocol has ended?
Williamson: It depends. One advantage of our multidisciplinary approach is that people tend to connect with at least one of us and stay in touch through that person. Most are followed by the neurologist. I frequently interact on an ongoing basis with HD families because of the reproductive issues. For our AD patients, the goal is for them to stay with the ADRC. One family called me recently. I had facilitated the testing and they called back later about applying for disability and adding the test result and the diagnosis. Their first application was denied and they hoped that the added information would help.
We have many EOAD families for whom we have not found a mutation. Some of them choose to participate in research, and we check in with them once a year in the course of those studies.
ARF: When an asymptomatic relative of someone with EOAD wants testing, what do you advise?
Williamson: We need a confirmed mutation in an affected individual to do genetic testing in an asymptomatic relative. Otherwise we are not sure how to interpret the presenilin result properly. Plenty of people call me who have a history of EOAD but no affected member is alive for testing first. I can offer counseling but no testing to those worried relatives.
ARF: What are the important dangers? That is, what not to do?
Williamson: Number one: Jump into testing without proper informed consent and genetic counseling. Number two: Test patients who do not have a family member accompanying them. The patients I work with are still able to make decisions, but they are going to have trouble remembering things from session to session. We can still talk about complex issues, the patient understands them in that moment, and certainly we include a lot of repetition to make the most of the patient's remaining abilities, but you need to have someone there to really understand permanently the import of what a genetic diagnosis means for the rest of the family and to take care of the concerns for the kids. It is such a hard diagnosis, and when you add the layer of the kids having to deal with it, too, it really requires a support person.
ARF: What repercussions does a genetic diagnosis have for a symptomatic patient? Treatment options do not change.
Williamson: Life issues do. Recently I had someone who called me to say, "Now I know I did the right thing to leave work." It was so hard for him to give up being the breadwinner. He felt irresponsible leaving his job. Getting the result affirmed his decision. It offered some level of acceptance and proved it was not his fault. He needed an objective result to solidify the clinical diagnosis and accept the doctor's advice. With proper counseling, most outcomes are good in some way. I have no bad outcomes in eFAD.
ARF: Is the risk for that more acute in presymptomatic carriers? After all, a diagnosed patient already knows at some level.
Williamson: Yes, predictive testing has a greater risk for adverse psychological events. I don't have people knocking down my door for predictive testing. They know this will be hard, and many do not go beyond the first counseling session.
ARF: What fraction of candidates choose predictive testing?
Williamson: In 8 years, I have done plenty of counseling, but few people went through with predictive testing.
ARF: Why not?
Williamson: Because there is no intervention. Maybe it is the way I present it in the counseling. The way I present it is, There is no prevention; there is nothing we would do differently once you know.
ARF: What if you told them there is a prevention trial of an experimental medicine that you could enroll in?
Williamson: As soon as we have something real to prevent the disease, predictive genetic testing for AD will be truly valuable. But in the meantime, we need to be cautious. Many people want to be proactive. I often get calls from relatives who want the test so they can adjust their financial planning for their children. To them I say, Do that anyhow. Estate planning is not enough reason to want to find out.
ARF: Could people join research while steering clear of the psychological consequences of knowing? Can they take the test so the study can put their data in the right group but not learn their results? They could still donate blood and CSF and undergo neuropsychological testing each year?
Williamson: We hear from many people, late-onset or early onset families, that they are willing to take the test and participate in research but do not want to know anything. But we have others who are not willing to even participate if they don't get information about their status back. Right now research at Columbia, and at some other academic centers, is set up so we do not give the participants feedback. If people want feedback about their neurological status, or if genetic testing is appropriate for them and they want it, they need to do it through our clinical ADRC setting, not through the research programs. The consent of our research studies does not include disclosure of genetic test results. If someone wants to know, we would repeat the test in the clinical setting.
ARF: So the individual has to pay $1,000 to repeat the test, after having gone to the trouble of participating in research and even as the center already knows the result?
Williamson: Yes, and there are good reasons for that. You want the result to come from a clinically approved lab that has the necessary quality control in place. A laboratory must have CLIA certification in order to disclose genetic test results. It has to be accompanied by a report. In New York, this is quite stringent. Besides CLIA certification, you have to have an informed consent designed specifically for that test. If you test someone for several different genetic conditions, you have to obtain consent for each of them. Not every academic research lab can comply with all that.
ARF: Have some of your patients told stories of getting the runaround from primary care physicians (PCP) who do not think of AD when people in their thirties or forties come in with memory complaints and disorientation?
Williamson: Oh, yes. It takes people a while to get to the right place. Early onset familial AD, CJD, FTD are not on the radar of PCPs generally.
ARF: Let's talk about family dynamics. How do families deal with having eFAD in their midst? Are they ever uniform in wanting to know, or not, being open versus keeping it private? Or do some siblings want testing, others not?
Williamson: It is a very individual decision. Some come via research, find out that testing is available, and later we see that initially eager person who was going to get the whole family tested backpedal as the others break away. I do see siblings try to make the decision together when the question is, Should we get mom/dad tested?
ARF: How does coping differ by age and stage of life one is in?
Williamson: I have less experience on that with eFAD than with HD. In HD, I see those differences. The 20-year-olds can be all over the map. They feel that this test is going to tell me if I will have kids, or how I will have kids. It will tell me if I am going to get married or not. They want the test to help them make decisions about their future. For people getting closer to their family's age of onset, the anxiety about getting sick is intensifying and they just cannot stand it anymore. For them it's the need to know.
ARF: Do you know of people who have chosen preimplantation diagnosis?
Williamson: For HD yes, for eFAD not yet at our center. Our team just had a conversation about this. The more we discover CJD, FTD, and eFAD families, the more we are going to see this desire and help the families with it. There is one eFAD case in the literature, and it raised quite a controversy (Verlinsky et al., 2002; Spriggs, 2002). Some of the editorials in response to the original article were stridently critical.
ARF: Some carriers I know decided to find out their status for family planning. They were not going to have kids if they had it. They were positive. Two years later, they got pregnant.
Williamson: That happens all the time in my HD group. People are so passionate in saying, "We are not passing this down to the next generation." Then they get pregnant. First, I asked myself what I have done wrong. But it is such a deeply personal issue, whether to have a child or not. The way I counsel families is, all you need me to tell you are your options. None of the options are easy. I have found that people do not blithely decide to just have a baby. It is a deeply felt decision they arrive at after much time and reflection. I see how hard it is for people to terminate a much-desired pregnancy. It is also really hard to go through preimplantation genetic diagnosis. When people first hear about it they usually say, This is it, this is our solution! But it is so difficult financially, emotionally, and physically, and success is far from guaranteed. It's sad to think that people who really want a child will not have one. Couples need to be informed and talk about it. If they cannot talk, I refer them to a family therapist. And then they have to live with their decision, not look back with regret.
ARF: One carrier told me, "I wish that my mother, had she known she has this mutation, would still have decided to have me." They see value and meaning in a curtailed life with a sad ending.
Williamson: I see that, too. People talk about how having this disease in the family has made them more compassionate. About how they like who they are even as hard as this is. You meet these people and they are wonderful and beautiful, and why should they not have a child? On the reproductive questions, my job is to help people learn about what their options are and guide them through the process as best as I can, but I cannot make the decision for them.