Diagnosing hATTR Amyloidosis: Family History

John L. Berk, MD: So Dr Polydefkis, at Johns Hopkins Medicine, how often are the orthopedic surgeons actually sampling a little bit of retinaculum with Congo red staining?

Michael J. Polydefkis, MD: Historically, it wasn’t done very much. But increasingly, it’s a topic of discussion. Some orthopedic surgeons are now doing that, but not all. Building on what Jim was saying, this is a very variable disease. So it’s difficult to come up with a prototypical case. Some patients may have prominent heart manifestations, prominent neuropathy, or all of the above. So it’s very variable and that can make it a challenge at the early stages.

John L. Berk, MD: And what are your 2 favorite signals of familial polyneuropathy?

Michael J. Polydefkis, MD: I think a family history is really helpful. You have to dig deep sometimes. It’s not always just a family history of neuropathy. You also want to ask about cardiac disease, unexplained death, cardiac death, arrhythmias. Sometimes people develop neuropathic symptoms, and it’s not labeled as peripheral neuropathy. It might get mislabeled as motor neuron disease or a mysterious wasting disease. So I think delving into the family history can be helpful. And then, as Jim alluded to, carpal tunnel syndrome. And not just unilateral but bilateral, presenting in a person 50 or 60 years of age, is a big red flag or clue.

John L. Berk, MD: Akshay, you’re involved in clinical trials of cardiomyopathy. You have a lot of experience in hereditary cardiomyopathies. We’ve talked very briefly about issues of penetrance that people who are anticipated to have clinical disease, because they’re genotypically positive for a particular disease, do not always express. Could you give us some perspective, from your cardiomyopathy expertise, on whether family histories are reliable in distinguishing familial versus sporadic disease?

Akshay S. Desai, MD, MPH: Well, for the reasons that Michael outlined, I think family history, although we can acknowledge it’s important, is always a little bit challenging. Not all patients recollect the details of family history. I think one has to be alert, as was outlined, to some of the things that would raise suspicion for cardiac disease—for example, segregating in the family. Unexplained death is a nice flag, because sometimes those deaths are sudden and might have been described as cardiac disease in a time where there may not have been deliberate diagnostic efforts made.

I think, also, sometimes a history of device utilization, because conduction disease might be a manifestation of this problem in the heart. I think that would be helpful. So if somebody needed a pacemaker at middle age or had arrhythmias at middle age, that would be something to at least consider. I think the challenge with this disorder is that there is variable penetrance and not every carrier is, therefore, affected over a lifetime. We have some data from large community cohorts in which populations at heightened risk—for example, African American patients carrying this amyloidogenic variant, V122I, have been followed over time. In that population, which represents maybe 3% to 4% of the total population of patients in the cohort of African Americans in the study, the patients who carried the mutation were certainly at heightened risk for development of some cardiac manifestations and particularly heart failure later in life, much more so than the noncarriers.

And so it’s clear that there is something concerning about carrying the mutation, but the actual clinical penetrance of the cardiac phenotype, even in patients at high risk for development of that, is not complete and may be less than 50% by the age of 70 or 80. So it’s a bit hard to know exactly who, in front of you, carrying a variant, is going to develop cardiac manifestations. The family history is a clue but is not always obtainable, and I think we have to kind of be mindful that just carrying the gene doesn’t necessarily imply that you’ll go on to develop the problem.