Analysis on the prevalence of hereditary ATTR amyloidosis.
John L. Berk, MD: The next topic to consider is: how many people are out there with hereditary TTR amyloidosis [hATTR]? I’d like to refer to the panel here to get perspective on this because it’s not clear. Dr Polydefkis: what’s the Baltimore, Maryland view of the world’s numbers of hereditary TTR, and particularly the polyneuropathy expression of that disease?
Michael J. Polydefkis, MD: It’s like you said; the exact numbers aren’t known. It’s estimated that globally there are about 50,000 cases. In the United States, it’s estimated that there are between 10,000 and 15,000 cases, of which a subset have been identified, about 3000 patients.
John L. Berk, MD: Dr Brannagan, does that sound right to you, or are there a bunch of people hiding in plain view?
Thomas H. Brannagan III, MD: I do think it’s an underrecognized disease, though the number of 50,000 with ATTR amyloidosis and maybe 10,000 with neuropathy worldwide is often cited. The V122I mutation, which predominantly affects the heart, but also does affect neuropathy, is seen in about 3% to 4% of African Americans. We see that very frequently here at Columbia University Medical Center. Within neuropathy centers, our own data and a Mayo Clinic series have found the Ala60 mutation is very common. Very frequently we see people who have been considered to have other neuropathies: idiopathic neuropathies, sometimes treated unsuccessfully for CIDP [chronic inflammatory demyelinating polyradiculoneuropathy], where we discover this mutation. I do think it’s an unrecognized disorder.
John L. Berk, MD: Dr Dyck, you’re way out in Minnesota. Is this a diffuse distribution of disease, or are there foci of neurologic disease out there that we should be looking for?
P. James B. Dyck, MD: Clearly there are endemic areas around the world for hATTR, such as Sweden, Portugal, Japan, and others. In the United States, it does not seem to be that we have definite centers. Most cases that we are going to see in the United States are not going to have a good family history.
Whereas if you go to areas in Portugal, it’s well known to run in families, and you’re going to identify it in endemic areas. In my practice, I have to keep an open mind as people with peripheral neuropathies walk through my front door, that hATTR may be the cause of that neuropathy.
John L. Berk, MD: Dr Polydefkis, do you agree that it’s sort of an equal distribution throughout the United States, or are there communities that are ripe with disease?
Michael J. Polydefkis, MD: In Mayo, and I think west of Mayo, we have a number of families with 1 variant, leucine 58 histidine. I generally agree that hATTR is spread throughout the country, and furthermore we have many different variants. It’s not Portugal where V30M is predominant. We see all variants in the United States. We’re a melting pot, and in that sense that makes it more of a challenge because different variants can have their own fingerprints. Of course when you see all variants, you lose track of those distinct presentations.
John L. Berk, MD: OK, thank you. Dr Witteles, we’d like 2 things from you: a reflection on the West Coast view of distribution of disease for polyneuropathy, and then I’d ask you to comment on the difference between the numbers for TTR cardiomyopathy as opposed to polyneuropathy.
Ronald Witteles, MD: Sure, thank you. From a West Coast perspective, I would say much like I think in every part of the country, by far the most common form of the disease is the V122I mutation that was referenced before. These numbers are quite clear from active large data sets in about 3% to 3.5% of Americans of African descent. As was referenced before, they tend to have very little phenotypic neuropathy. If you look closely you can find it, but at least for heterozygote individuals, which is the majority of course, they tend to have very little clinical neurologic phenotype. If we look for the patients with true clinical neuropathy then, as Dr Polydefkis was saying, it’s a mixed bag. You see some of the Ala60 mutations, some of the V30M mutations, and then a host of unusual mutations that might be specific to just individual families, but add up to a reasonable percentage.
That gets to the second point that you were getting at, which is that in this country the cardiovascular phenotype is by far more common than the neurologic phenotype. That’s of course true when you count the wild-type patients, who are not the focus of what we’re talking about today, but are clearly the majority of patients who have ATT or amyloidosis. But it’s true for the variant or hereditary ones as well, because again of the dominance in this country of the V122I phenotype. Whereas I think this is still an overall quite uncommon, though very important to recognize, disease on the neurologic side, in the right population it’s downright common on the cardiovascular side.
John L. Berk, MD: Thank you very much, Dr Witteles. Dr Brannagan, in the major phase 3 studies that have been conducted or are in progress, where the enrollment is targeting people with polyneuropathy, specifically peripheral neuropathy; what percentage of those people also have evidence of cardiomyopathy?
Thomas H. Brannagan III, MD:I believe in the Ionis Pharmaceuticals, Inc inotersen study and the APOLLO patisiran study, it was about 60% of patients who also had cardiomyopathy.
John L. Berk, MD: OK, that’s great. Dr Dyck, can you give us a bit of insight as to where the more prevalent mutations in the United States have come from? That may give us some perspective on family history.
P. James B. Dyck, MD: Where the more prevalent mutations have come from, you mean geographic locations?
John L. Berk, MD: Yes.
P. James B. Dyck, MD: There may be data about that; I’m not so familiar with data suggesting that areas in the United States are more prevalent than other areas. That isn’t the case in my own practice. Early on, before we really understood what this was, we talked about the Indiana type and things like that, so there were recognized places where it did seem to come from. In my own practice, I see people from all over the country come in. There are certain features of neuropathy that make me think this is more likely to be hATTR: they have pain, autonomic features, weight loss, and weakness. When you start getting those features occurring in the same patients also with a history of carpal tunnel syndrome, also with a history of lumbar spinal stenosis, you then start thinking much more highly about this. I think the real challenge for us neurologists is the early onset disease, because early on hATTR looks very much like a lot of other neuropathies.
John L. Berk, MD: Great. We’re going to expand on many of the points you’ve just made. Dr Polydefkis, where have some of these mutations originated around the world?
Michael J. Polydefkis, MD: In the United States, as has been said, V122I is the most common. That has been isolated to the coast of Africa. T60A is also very common and is felt to originate from Ireland, and V30M is very common as others have said. The hotspots for V30M around the globe are Portugal, Scandinavia, Brazil. Then the rest is a mix of a number of different genetic variants.
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Transcript Edited for Clarity