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Understanding Hereditary ATTR (hATTR) Amyloidosis and the Recent Advances in Management - Episode 4

Uncommon Presentations of hATTR Amyloidosis

John L. Berk, MD: Undoubtedly, with the experience you’ve had at Johns Hopkins Medicine and at the Mayo Clinic, there have been unusual presentations of familial amyloidosis. Could you share with us, perhaps, some of the ones that strike you, that are not of the usual paradigm of sensory-motor and autonomic dysfunction?

P. James B. Dyck, MD: Well, I think when you see somebody who presents with all 3 of those, that’s fairly typical. But you can see people who will present as a motor neuron disease. They look like they may have ALS [amyotrophic lateral sclerosis], and they turn out to have amyloidosis. Similarly, you can see people who present with pure autonomic neuropathy, and they turn out to have amyloidosis. And so I think it’s those sort of presentations that are often confusing.

One of the big things that has become very apparent across the world is that a lot of amyloidosis is misdiagnosed as CIDP [chronic inflammatory demyelinating polyneuropathy], which is a demyelinating polyradicular neuropathy, meaning that there’s a weakness in proximal and distal muscles.

Severe amyloidosis absolutely can present in that phenotype, but very rarely does it really have demyelinating features on electric physiological testing. People often ask, “Why is it so often confused to be CIDP?” I think it’s more because neurologists around the world want to find a treatable cause of neuropathy. And so they misdiagnose CIDP and most neuropathies. Mini neuropathies are called CIDP when they really aren’t CIDP. Some cases of TTR [transthyretin] amyloidosis absolutely look like CIDP, but I think most don’t.

John L. Berk, MD: The polyneuropathy with familial transthyretin amyloidosis [ATTR] is a length-dependent process. Are there mutations that present with, primarily, upper-extremity manifestations, or is that inconsistent with the disease?

Michael J. Polydefkis, MD: It can be fully consistent with the disease, and the biggest example would be carpal tunnel syndrome. Patients can develop early and pronounced carpal tunnel syndrome, and it can be mistaken either for carpal tunnel syndrome itself or motor neuron disease. So it certainly can present as an upper-extremity predominant form. I’ll also echo what Jim touched upon. I’ve had several cases that, for all the world, looked exactly like CIDP—you know, electrophysiologically, clinically. But only the lack of response to treatment or a family history prompted us to think about hATTR [hereditary ATTR]. So it can present as a classic demyelinating neuropathy.

John L. Berk, MD: Not to be too provocative, but is there a reason, then, that perhaps when CIDP is being considered as the diagnosis, there ought to be genetic testing to be sure that a case of ATTR is not being missed?

P. James B. Dyck, MD: In most CIDP, no. Again, it may be a little off topic here, but in general, CIDP presents as a motor predominant polyradiculoneuropathy. I think the testing you want to do is monoclonal protein testing because they can be associated with that. The big one is POEMS [polyneuropathy, organomegaly, endocrinopathy, monoclonal plasmaproliferative disorder, skin changes] syndrome, which usually will present with a lambda monoclonal protein.

You want to do an HIV test. One can say you can do a genetic test. I don’t think that would be the wrong answer, but it’s certainly not in my practice. You put a person on treatment and, very quickly, they respond. The treatment usually is intravenous immunoglobulin or prednisone or plasma exchange. I think when they don’t respond to that conventional therapy within a couple of months—3, 4 months—then one certainly should think more broadly and do genetic testing. And potentially, a nerve biopsy is a good thing to do. It’s not just amyloid you’re thinking about at that point either. There are other things as well.

John L. Berk, MD: I would like to add that there are other organ manifestations of TTR, and it’s important to keep them in mind. We have a series of urogenital amyloid at Boston University spanning 3 decades. And in that population is a subgroup that is TTR. So people may present with hematuria and, on biopsy of the bladder, demonstrate amyloid. It’s really critical that the audience understands that it’s not sufficient simply to diagnose amyloid. You have to know what the amyloidogenic protein is because that’s what defines the clinical course and the therapeutic options. So that really is quite important.