Current Series: Understanding Hereditary ATTR (hATTR) Amyloidosis and the Recent Advances in Management

John L. Berk, MD: In cardiology with cardiomyopathies, the frequency with which you use genetic panels to help identify the actual process…Is that a reality, and is that something we should be adopting for the evaluation of neuropathic patients?

Akshay S. Desai, MD, MPH: I think we’re increasingly speaking more broadly than just hATTR. I think we’re increasingly looking to genetic testing to inform the evaluation of patients with cardiomyopathy and heart failure that’s felt to be familial. But we’re not yet ready to consider it routinely. I think that there are a few well-defined variants that are accessible by the panels and the yield of those panels has increased as we’ve had more defined variants available.

For patients with neuropathic disease in cardiomyopathy, I think the broad genetic screens have not been terribly informative. I think we’re largely relying on tissue sampling, and, then, genetic evaluation in those patients with a positive tissue diagnosis. I think broad screens have been a little low-yield in this population.

John L. Berk, MD: So neurologically, the perspective on genetic paneling as an effort to cut through the difficulties of diagnosis…Michael, your opinion? And then, Jim?

Michael J. Polydefkis, MD: So I think it is pretty low-yield. You asked earlier: Should we be testing every CIDP patient for hATTR? I think that’s probably a moving target. A year or two ago, I might have said no very quickly. Well, today I’m probably thinking about it much more. So I think specific targeted genetic testing makes sense. To do broad testing on every patient walking in the door—I don’t think it’s good enough yet.

John L. Berk, MD: Jim?

P. James B. Dyck, MD: It’s an important question. So we have developed, at the Mayo Clinic, a large panel for inherited neuropathy. Inherited neuropathy, hereditary motor inherited neuropathy, is called Charcot-Marie-Tooth disease, and I really think that hATTR amyloidosis is a form of Charcot-Marie-Tooth disease. It’s never been classified as such, but it absolutely is because it’s hereditary motor sensory neuropathy that’s inherited. So it is a form of that. And so, on that panel, hATTR mutations are listed. I don’t order that big panel if I think specifically about hATTR. But in people who I think have an inherited neuropathy, I have ordered that and it has been positive for TTR amyloidosis when I was just thinking of inherited neuropathy, more generally. So the answer is, no, I’m not going to do a big panel on everyone, but I certainly am going to do one on people I think have an inherited neuropathy.

John L. Berk, MD: OK. I think it's important to mention the counseling that's required for people who are undergoing genetic testing. The Alnylam Act and the Compass genetic testing that’s supported by Akcea are things that ought to be considered prior to people undergoing genetic testing. What sort of program is there at each of your institutions? So we’re talking about [The Johns] Hopkins [Hospital, Baltimore, Maryland], Brigham and Women’s [Hospital, Boston, Massachusetts], and Mayo Clinic [Rochester, Minnesota]. Michael?

Michael J. Polydefkis, MD: So genetic testing and genetic counseling go hand-in-hand, and the Alnylam Act and Compass programs give access to genetic counseling. But within Hopkins, we have our own genetic counselors who are certainly available to patients and patients are referred to them. It happens with every patient.

John L. Berk, MD: Akshay?

Akshay S. Desai, MD, MPH: Yeah, I think we would not undertake to arrange broad panel genetic screening without genetic counseling prior to even initiating the test. So the path to genetic counseling in our cardiomyopathy program due to genetic testing rather goes through the genetic counselors. So the blood sample or other tissue sample is obtained only after that conversation with a dedicated counselor has occurred. We feel that those 2 are 1.

John L. Berk, MD: And why is it such a big deal? What’s the issue?

Akshay S. Desai, MD, MPH: Well, I think the issue is, in part, there are few that I can imagine. One that we are very concerned about is that the information that’s returned from the genetic test is received in some context. So there should be some pre-screening guidance about what the likely results are from genetic testing, how certain they are, and what the implications are with regard to what we’ve talked about—penetrance, for example, of a positive test. I think about what the implication would be of a negative test for a certain diagnosis, and also, what would be the result of some indeterminate variance that kind of come back on some of the screens? I think the other is to help people understand what the implications might be for life insurance and other things of that nature that may be uncovered. So I think with pre-genetic counseling, helping people to understand why we’re doing the test, what the potential results would look like, what the results will imply for the residual life and also for treatment, and then also what the uncertainties are in the testing is important.

John L. Berk, MD: Jim, any comments to add to that?

P. James B. Dyck, MD: No. I think genetic counseling is very important. We have that at Mayo Clinic as well, and I agree with my colleagues.

John L. Berk, MD: The efforts to overturn the ACA [Affordable Care Act]: What potential impact is there for people undergoing genetic testing?

Michael J. Polydefkis, MD: Being labeled with a disease, or being at risk for a serious disease has many implications for insurability, employability. So it gets complicated quite quickly.

John L. Berk, MD: Yeah, I believe nationally medical insurability is guaranteed under the ACA. But if that’s overturned, then protections would potentially be lost. Long-term disability and life insurance policies are genetically protected on a state-by-state basis. So depending on where you live, it may significantly affect your ability to implement those policies after a genetic test reveals some disease.