Roy E. and Merle Meyer Professor of Neuroscience, and director, Peripheral Nerve Research Laboratory, Mayo Clinic

P. James B. Dyck, MD

Dr Brannagan, what is the therapeutic future that you foresee in the next 2 years? Then I’m going to ask Dr Witteles what the therapeutic future is in 10 years.

In the next 2 years, hopefully vutrisiran looks promising to be approved, and the cardiac studies hopefully should be completed and moved forward. As was mentioned, Ionis Pharmaceuticals, Inc has a monthly subcutaneous product that, with the data so far, is thought not to cause the platelet and glomerulonephritis that requires the frequent monitoring. I think there will be easier-to-use medications available in the next 2 of years.

There is interest in some more novel approaches. For example, there’s interest in gene editing because you have this disease that’s usually from a single point mutation, and if gene editing is going to work in anything, this might be where it is. There has been an early look into that. There are still some attempts with antibodies for amyloid removal. I would say as a rule, those efforts in amyloid disease have been relatively underwhelming to date, but they’re still being investigated. There might potentially be something there. But I think it’s going to be more about better and easier-to-take ways of these sorts of approaches that we see now. It’s going to be hard to beat the results that you saw with patisiran and inotersen, in the way that they were able to halt progression of the disease and perhaps even improve it. It is going to be more about early diagnosis, better ways of delivering the therapies, and hopefully much more cost effective; right now the cost is really high for all of these treatments.

Dr Polydefkis, you’ve got a PhD degree. Can you live without TTR?

I don’t know if you can live without it, but you could live with a lot less than you have.

So you have no concerns about gene editing to eliminate or suppress its production. Do you have any concerns about 

We accept patients who have been on therapies for upward of 6 years. Very detailed investigations, including looking for evidence of vitamin A deficiency, have shown no signal of toxicity.

Dr Dyck, in wrapping up here, how would you guide neurologists who are concerned that maybe they’re missing the diagnosis of hereditary TTR, peripheral and autonomic neuropathy?

We already touched on this, but I think the easiest thing for them to do is a gene test. That is certainly a way that they won’t be missing these patients. The question is should we be doing this in every single patient with neuropathy who walks through our door, or how often do we do it? My involvement in all these different studies really opened my eyes to the range of severity of the neuropathy. At its mildest, it’s a very nonspecific axonal neuropathy, and then at its severest, it can look like CIDP [chronic inflammatory demyelinating polyneuropathy]. It can be a motor polyradiculoneuropathy, it can be almost a pure autonomic neuropathy, or most commonly it is a mixed pain, numbness, weakness, autonomic with cachexia. It’s quite easy to see there, however early on it’s not easy to see; the easiest way to pick those up is genetic testing.

Dr Brannagan, do you have any advice for community neurologists?

There have been a couple of papers published that highlight red flags that I think are often useful to think about when considering who to test. There’s estimated to be 20 million people in the United States with peripheral neuropathy, and whether all of those 20 million people need to have genetic testing is unclear. I’m not sure I would advocate for that, but it definitely is a disease that gets missed. The red flag points are useful to think about: if there’s a family history; if there’s bilateral carpal tunnel syndrome; alternating diarrhea or constipation, which in my experience often doesn’t get put together with neuropathy; the heart failure with preserved ejection fraction. Also rapidly progressive neuropathies, or neuropathies that have failed previous attempts at treatment, are some of the points in those red flag papers, which I’ve found to be useful in communicating with people.

Dr Witteles, understanding that you’re not a neurologist but you do deal with patients with amyloid and carpal tunnel, what’s your advice for physicians in the community who are pursuing carpal tunnel release surgeries? Is there any other management of those procedures that might inform us about disease?

There have been a couple of nice studies that have now looked at this. If at the time of surgery a bit of ligamentous tissue is sent to pathology specifically for red staining, you can find amyloid deposition in maybe up to 10% of these cases, not all ATTR, although mostly ATTR and usually preceding any other clinical involvement of the heart, or nerves, etc. There’s certainly a case to be made to speak to your hand surgeons, or orthopedists, or whomever is doing it to say, “Hey, start making this standard practice.” Typically with most carpal tunnel release surgeries that are done, there’s nothing that is sent to pathology, and it could be missed. Again it’s low-hanging fruit; I’d say that isn’t widespread but hopefully may become that.

Well gentlemen, it’s been a real pleasure spending time with you. I look forward to having a beer when the pandemic is not such a challenge. Thank you very much for your thoughts, and stay well.

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Videos

Analysis of current and newer therapies for the treatment of hereditary ATTR amyloidosis. 

Future Treatment of hATTR Amyloidosis

There has been some exciting top of the line results shared by Alnylam Pharmaceuticals, Inc on a study named HELIOS-A looking at a drug called vutrisiran, which is a second-generation 

gene silencer. There is hope for it to be the new and improved patisiran. Dr Brannagan, what were your thoughts about the press release for vutrisiran?

It seemed like exciting data; I would like to see more of it, but at 9 months there was already a difference between the placebo arm and the active drug. This was true of patisiran as well as inotersen. They also reported that there was a very good safety profile. It was thought at the time of the study that is was unethical to have a placebo arm, therefor the study compared the drug to the historical placebo from the patisiran APOLLO study. However, there was an active comparator arm with patisiran, and I did not see data in the press release about how the new drug compared to patisiran; I would be interested in that.

Dr Polydefkis, let’s say you’ve got patients who are on patisiran and they’re getting intravenous infusions every 3 weeks. Vutrisiran sails along and meets FDA approval; what’s the future for your patients on patisiran?

 First, we’ve been a little bit spoiled. Here’s this terrible progressive disease, and we have yet another drug that I would characterize as another grand slam. We’re becoming spoiled with all this success. The data that were announced are not complete, but it does look remarkable. The difference at 9 months was on par with what we see in the APOLLO-B study; it looks very similar. Would I switch patients? Again, I think it’s a discussion with the patient. However, the once every 3 months subQ [subcutaneous] injection does sounds better than an infusion every 3 weeks.

Reported were quality of life, gait speed, and the neuropathic measures. Dr Witteles, I’m really going to stretch you on this one. There was a mention in the press release that NT-proBNP [N-terminal pro-B-type natriuretic peptide] improved, or that there was movement in an improving direction. Is that surprising to you? How does that fit with your concepts of TTR protein stabilization with tafamidis?

It’s certainly not surprising in the context that patisiran clearly did that in the APOLLO trial. In the APOLLO trial they had a subset of patients who had clear evidence of cardiac involvement who were preidentified. On average in the placebo arm, their NT-proBNP went from about 700 to 1100 [pg/mL]. In the patisiran arm, it went from about 700 to 600 [pg/mL]. Frankly, it would have been surprising just based on mechanism if the vutrisiran showed anything different. In the cardiac world, there are phase 3 studies with vutrisiran as well as the next-generation form of inotersen going on as we speak. I believe all of us are extremely excited about their potential for the cardiac form of the disease based on how the disease works; it would be shocking if they weren’t effective

Expert discussion on the recent topline results released for vutrisiran in the HELIOS-A trial. 

Evaluating the Potential of Vultrisiran 

Dr Polydefkis, Dr Witteles suggested that the earlier the better with most effective therapy, alluding to 

 gene silencers. Let’s say I have fairly advanced, previously undiagnosed TTR amyloid neuropathy. I’m seeking your advice; am I out of luck in terms of getting benefits from the 

No. It’s been shown that irrespective of neuropathy severity, you’ll still experience a benefit from silencer therapy. This means that your disease will be likely halted. You may not improve dramatically, you may not go from a cane to running marathons, but you won’t regress to 2 canes or to a wheelchair.

Discussion on the role of TTR protein stabilizers and gene silencers for treating hereditary ATTR amyloidosis. 

Benefits of TTR Gene Silencers 

 Dr Dyck, help us here. Dr Polydefkis said there was a 28-point worsening of neuropathy in the placebo group of the APOLLO study and a 6-point actual improvement of scores from beginning to end of study in the treated group. What does that mean? How do we interpret the complex and comprehensive scoring system?

The Neuropathy Impairment Score [NIS] troubles people because they don’t know what it means. Simply, it is a measurement of patients’ deficits on a neurological examination. It’s weakness, it’s reflex changes, and it’s sensory loss, and it’s adding those together into a score. An NIS score of 50 is a moderate neuropathy; 100 is a severe neuropathy. A worsening of 28 points is a big deal. That was part of the point I was making earlier: The reason these studies were able to be effective is that patients with this disease worsen fairly dramatically over time.

Can you give us an idea of what the difference would functionally be if I’m in the study and I worsen by 28 points?

That might mean that you went from walking independently to not walking; it is a big difference. Improvement of 6 points is a real improvement. People always want to make head-to-head comparisons between these 2 studies. I always try to avoid doing that. The reason is 1 study went for 18 months; the other went for 15 months. They also used slightly different end points, and they allowed slightly different degrees of severity in neuropathy of the patients who went in there. It is a mistake to say that 1 drug is better than the other because there are these differences in the studies.

The thing that is very clear about both studies is that they’re both home runs. Both drugs work incredibly well. Both not only stop progression of neuropathy but had sizable numbers of patients in the study actually having improvement. To me, the big difference really has to do with the adverse-effect profile. One advantage of inotersen is that it’s a subcutaneous drug; patisiran is an intravenous drug. Inotersen had the thrombocytopenia, so that was a real potential problem. Since they have begun a surveillance program, they really stopped that problem with the thrombocytopenia. From my perspective, it really comes down to patients’ convenience about which of these drugs is better. If a subcutaneous drug is better for you, you might want to go with inotersen. If you’re not bothered by the intravenous route, you have less monitoring and fewer potential adverse effects with patisiran.

Dr Polydefkis, how do you decide between these 2 agents when prescribing TTR [transthyretin] gene silencer?

It is a discussion with the patient. We talk about many of the things Jim just touched upon: the route of administration, subcutaneously vs intravenously; the frequency, weekly versus every 3 weeks; and the need for monitoring. That discussion leads to a mutual decision.

On the West Coast, Dr Witteles, even though you’re a cardiologist, you’re an honorary neurologist because you’re codirector. How do you guys differentiate between these 2 agents? Or do you simply leave it up to the patient?

I’d follow somewhere in between that vs paftisiran clearly being superior. I agree that they were different trials. Unless you have head-to-head in a given trial, there’s never going to be a perfect comparison. We have the data that we have. You can even extend it to some of the substudies like the cardiac side. In APOLLO you did see some clear improvement from a cardiac side, which was not so clear in the inotersen study. When you look at it all, if you had to bet if 1 of them was a bit more efficacious than the other, the answer would be yes; it seems like patisiran was a bit more efficacious. Is that as good as a head-to-head study? Of course not, but those are the data we have.

Then you do have those safety issues: the thrombocytopenia, glomerulonephritis, and a little imbalance that wasn’t statistically significant but that was still notable on deaths. I put all those together. Though I discuss both options with patients, I generally recommend patisiran for them unless the IV [intravenous] infusion or the premeds are going to be a specific problem. For the big picture, I agree entirely with Dr Dyck. The big takeaway is not which is better. It’s that, my lord, these were both grand slams, not just home runs. They were both incredible, and the biggest thing is to get somebody on 1 of these 2 agents as soon as you can when you make the diagnosis.

Dr Brannagan, do you use any TTR protein stabilizers for your patients with neuropathy? Dr Witteles is saying that’s a waste of time.

Hold on, I didn’t say that. No, I don’t believe that at all.

I do certainly have patients who are on these medications, and I work closely with our cardiologists. There are some data that have shown a survival benefit with stabilizing drugs. I have to say, I’m not entirely certain that combining a silencer and a stabilizer is necessarily more beneficial. However, there are not survival data with the RNA silencers, and there are, including your own work, with the stabilizing drugs. I certainly have people who are combined. We also sometimes use the stabilizers, particularly diflunisal, when people don’t have neuropathy and don’t have cardiomyopathy but do have carpal tunnel, which is from amyloid, as a preventive medication. We usually discuss with them that there are no clear-cut data, but that it’s potentially a treatment. Studies on this area need to be done, but at this moment when we don’t have studies, we sometimes do that.

I want to interrupt here because I know Dr Berk is not going to toot his own horn. I’m going to toot his horn. He did a very nice study with my father on the use of diflunisal in hATTR [hereditary transthyretin-mediated amyloidosis]. He showed, very convincingly, with the modified Neuropathy Impairment Score + 7 that diflunisal slows the progression of hATTR polyneuropathy. It’s a very important study, and I do think the role of membrane stabilizers should still be considered. Some sort of cocktail may be the ultimate answer, but we don’t have that data. We should not abandon diflunisal or tafamidis.

I agree with that entirely. In fact, we try to get most of the patients on a stabilizer who are on patisiran or inotersen as well if they have clear cardiac involvement, as long as they can have it paid for and it’s not huge out-of-pocket expense. I do tend to try to get them on both a stabilizer and a silencer, so tafamidis plus most of the time patisiran or inotersen. In the absence of being able to do so, unless they have a contraindication, I do usually put them on diflunisal. As was said, do we know that diflunisal plus a silencer is better than a silencer alone? No. For people who have real phenotypic neurological involvement and cardiac involvement, if it’s 1 of 2 I can choose, I will definitely go the silencer route because we know that the difference in the progression of their neuropathy is so much dramatically better with a silencer vs the stabilizers.

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Clinicians elaborate on key trial data revealed through the APOLLO and NEURO-TTR studies in hereditary ATTR amyloidosis. 

Evaluating hATTR Amyloidosis Therapy

Gentlemen, let’s turn to some therapeutics because that’s really the purpose of our discussion. The original intervention was orthotopic liver transplant. In a very simple and really courageous experiment, the idea being that the abnormal protein is being produced in the liver. If you change the factory, then you can change the course of disease. The earlier results were quite impressive: The abnormal protein was replaced by a normal protein, there was a normal TTR [transthyretin], and disease course seemed to stabilize.

The problem began about 5 years into the transplant experience when some ultrasonographers at BU [Boston University] reviewed data and found that hearts were progressing as if there had never been liver transplants; they looked like amyloid hearts. That spawned efforts to develop a medical approach to treatment of this disease. Through efforts and really the brilliance of Jeff Kelly, a physical biochemist in California, the idea of stabilizing TTR tetramers was born. By searching for thyroxine mimetics, developed some agents that are proven quite effective at altering the course of disease.

One problem is that while those agents rarely can fully stabilize disease, typically they simply slow it down. This has been evidenced not only in neuropathy experience but also in cardiomyopathy. That leads us to the primary discussion that we need to have: TTR gene-silencing drugs. Dr Brannagan, how do these TTR gene-silencing drugs work?

There are 2 medications: patisiran, which is a small interferon RNA treatment, and inotersen, which is an antisense oligonucleotide. They both stop the message RNA from translating the transthyretin protein, which is the protein that misfolds into amyloid. It actually stops the production not only of the mutated transthyretin but also the wild-type transthyretin.

Excellent. Dr Polydefkis, can you give us a review of the APOLLO data featuring patisiran? What struck you about that study?

This was an 18-month trial of 225 people randomized 2:1 patisiran to placebo; it showed a dramatic treatment effect. The primary outcome measure was a very rigorous neuropathy score that encompassed exam, nerve conduction, and other test results. It was wildly positive. The placebo group progressed 28 points on this scale of 304 points, and the treatment on the patients receiving patisiran improved by 6 points; that’s a big difference. A host of other secondary measures: the Norfolk Quality of Life [Questionnaire-Diabetic Neuropathy], walk speed, autonomic scores were also positive. In the world of peripheral neuropathy, this is really a remarkable test result, a wildly positive treatment effect. It spanned many domains of the disease.

That’s a great review. Dr Brannagan, you have been instrumental in the development and validation of inotersen. What results should we be most impressed by with that study? How does it compare with the APOLLO patisiran experience?

The studies were very similar. Patients were randomized 2:1 to the active drug, inotersen, compared with placebo. The placebo arm in that study, the patients progressed very rapidly. The outcome measures were very similar; both studies used the Norfolk Quality of Life score, and both studies used the modified Neuropathy Impairment Score + 7, even though they were slightly different scales. As Dr Polydefkis said, the modified Neuropathy Impairment Score + 7 was developed initially by Peter Dyck, the father of James Dyck on our call. It measures strength, sensation, and reflexes and also includes nerve conductions and quantitative sensory testing.

If you look at the study, the patients on placebo progressed rapidly on both the modified Neuropathy Impairment Score plus the Diabetic Neuropathy Quality of Life score, which has been validated in hereditary TTR amyloid. Patients who were on the active drug did much better compared with the progression. There was some worsening in the totality of the patients, though. I believe 36% of patients not only stabilized but improved on the Neuropathy Impairment Score, and about half of patients improved on the Quality of Life score.

Treatment overview of hereditary ATTR amyloidosis and considerations for using newer therapies such as patisiran or inotersen in appropriate patients.

Recent Advances in hATTR Amyloidosis Treatment 

Dr Witteles, you’re way out at Stanford. What’s the importance of typing the protein and how do you do it?

 It is extraordinarily important. If you’re biopsying, certainly on the cardiac side, by definition there’s some doubt as to what the type might be. If it’s ATTR [transthyretin-mediated amyloidosis] you can usually do it without even needing to biopsy. I am certain we all have stories of patients who have been treated for the wrong form of amyloid because either it wasn’t typed or it was mistyped. That is a dual tragedy from missing the opportunity to treat what they actually have and the toxicity of whatever treating they’re getting; you never want to make that mistake.

There are 2 main ways it can be done: immunohistochemistry or mass spectrometry. Without a doubt, the gold standard is mass spectrometry. As a general rule, that’s how it should be done. We have a world-class cardiac pathologist at Stanford. If he calls it [ATTR] off immunohistochemistry, I’m going to feel confident in what he says. That’s because he is an exceedingly experienced world-class pathologist and is not going to overcall or undercall. This is a high-stakes diagnosis to get right. Mass spectrometry is the gold standard; it can easily be sent out through referral centers like Mayo Clinic. In general, I would recommend that.

I’m going to ask you a quick question, looking for a concise answer. You’ve got someone who’s got AL [light-chain amyloidosis], and they develop cardiomyopathy. What’s your thinking? Is that always AL amyloid cardiomyopathy?

I’ll try to be concise. AL tends to go to whatever organs that particular light chain is prone to go and keep going there. If you have somebody who’s years into a diagnosis who previously had light-chain AL involvement of the kidneys who develops a new cardiomyopathy, I wouldn’t be certain of that. On the other hand, if somebody presents with proteinuria and a thick heart and they got a renal biopsy that shows light chain amyloidosis, I’m not biopsying the heart again or working up for other causes. Theoretically, can you have coexisting AL and ATTR? Absolutely, but it’s awfully rare, and it would really need to be like that first scenario for me to really chase it down.

The use of mass spectrometry is the gold standard in amyloid proteins. 

Identification of the Amyloid Protein 

All 4 of you have talked about the diagnosis of disease and the avenues that you pursue. Dr Witteles, can you give us your perspective on the need for tissue and what’s your favorite?

Sure. On the cardiac side, most of the time we can make this diagnosis without tissue as long as they don’t have monoclonal protein and they clearly have a positive PYP [pyrophosphate] scan. After you have made the diagnosis, now all you need to do is genetic testing to determine if they have a wild type or a hereditary form of the disease. If either the PYP scan is equivocal or there’s a monoclonal protein, then you have to move on to biopsy. My own general preference is to biopsy the clinically involved organ, which in my world is the heart. Doing so in good hands has a very low risk. It’s much safer than, say, a kidney biopsy. Unlike other infiltrative cardiomyopathies, it has nearly 100% sensitivity and specificity. What’s more is that you will get lots of amyloid there, so you can accurately subtype it and make sure you’re making the right diagnosis.

It is reasonable if places want to start with a fat-pad biopsy first because it is even lower risk and easier to do; it can be done in the office. However, it has a much higher false negative result rate, particularly in ATTR [transthyretin-mediated amyloidosis] as opposed to AL [amyloid light-chain amyloidosis]. If you’re ever going to do that and it comes back negative, you have to follow it up with further testing such as an endomyocardial biopsy.

All right, neurologists. Dr Polydefkis, you spoke about epidermal nerve fiber analysis and skin punch biopsies. Can you give us your perspective on sural nerve biopsies?

Sural nerve biopsies are fantastic; they pick up amyloid. It’s not 100% clear with cases with amyloid where it’s missed on a sural nerve biopsy, but it’s an excellent technique. If you have a high suspicion and you have a negative result, as Dr Witteles said: You don’t stop there. You would go further, whether that’s a skin biopsy, cardiac biopsy, fat pad biopsy, or other nerve biopsy; that is up for discussion.

Dr Brannagan, sural nerves. Do you do them?

I would say I do them. One situation that we do them not so much is somebody that we say has a gene test that then we want to confirm whether they have amyloid. Very often we do them when somebody has a significant or severe neuropathy, and we are trying to figure out why they have neuropathy. Amyloid is 1 cause of a severe neuropathy, vasculitis is another, CIDP [chronic inflammatory demyelinating polyneuropathy] is another for which we can usually identify a nerve conduction. Very frequently I’ve seen patients who are identified with amyloid because of the nerve biopsy and then we do the genetic testing.

If somebody has a mild, say, small fiber neuropathy and has a genetic test, I’m not always keen to jump straight to a sural nerve biopsy, which does have some morbidity. I would more likely do a skin biopsy that might show amyloid and also often can help document the presence of a neuropathy. Sometimes we do fat-pad biopsies, even though the sensitivity for ATTR is poor; I think it is in the 40%-to-50% range. I do sural nerve biopsies in some situations but not in all situations.

 As the head of the Peripheral Nerve Research Pathology laboratory, I have very strong feelings about this topic, and it’s near and dear to my heart. I am much more dependent on pathology than most of my colleagues here. We have a nice service run through the Department of Hematology at the Mayo Clinic where they do fat aspirates, we call them, as an easy test and essentially every patient who walks into my door with peripheral neuropathy gets a fat aspirate. It’s part of my routine work-up for peripheral neuropathy. I’m using that both for AL and for TTR [transthyretin]. I also will do a monoclonal protein study in all patients who walk through my door. I have not done genetic testing on all my patients, but I have started to do it at a higher and higher frequency.

I agree with Dr Brannagan that fat aspirate has a low sensitivity. At our institution it’s 50% to 60%. On the other hand, because it is not a very invasive procedure, I do it on most patients, realizing that I may miss patients. You asked about sural nerve biopsy. I do biopsy where there is involvement. If you have a general polyneuropathy, the sural nerve is a good thing; but in some amyloids it’s a multifocal process, and I will often do a targeted fascicular nerve biopsy from an MRI lesion. That’s much more likely in AL than it is in TTR, so it’s a bit of a different topic. However, I don’t restrict myself to sural nerve biopsies and look because, I often will use it with imaging. Then we do lip biopsies as well, which I don’t think we’ve mentioned, as well as epidermal nerve fibers. Salivary glands are another good tissue to go after.

Parenthetically, can TTR amyloid can have associated myopathy in your experience, Dr Dyck?

Thank you for asking that. We’ve recently written a paper about coexisting TTR myopathy. Yes, you can do a muscle biopsy too. However, the TTR myopathy is much less frequent than the TTR neuropathy.

Various types of biopsies to diagnosis hereditary ATTR amyloidosis are discussed.  

Tissue Biopsies in hATTR Amyloidosis  

Dr Brannagan, you mentioned genetic testing, and both Alnylam Pharmaceuticals Inc and Akcea Therapeutics, Inc have programs. Do you use those programs? If not, how do you do your testing?

Actually, I have been using their testing, and it’s very useful to screen for; I believe the Alnylam program uses Invitae Corporation. I believe they have 73 genes for inherited neuropathies. The Ionis Pharmaceuticals, Inc program, which uses the Compass program, has 80 genes; it’s actually very easy to use. We do genetic counseling beforehand, and then the patients, if they agree and consent, can either get a blood draw or a spit test. Usually the turnaround on the testing is about 3 weeks. It is a next-generation test. This does not relate to amyloid, but they actually have very good coverage for 1 very common inherited form of Charcot-Marie-Tooth disease, which is actually a duplication and a deletion unlike many other next-gen programs.

Let’s talk about genetic counseling. Why do we need to be concerned about genetic counseling? It’s a genetic disease; it’s important to make the diagnosis. What’s with counseling?

It’s a good idea to do counseling in both symptomatic and also asymptomatic patients. In my opinion it’s important in both, but even more important in asymptomatic patients. Frequently we have a family member who wants to have their family members tested, and there are some implications of the testing that often we can spend some time with. The genetics counselors are particularly trained to explore patients’ personal thoughts on the impact of a positive result as well as the impact on life insurance, disability policies, and so forth. I strongly encourage it. In New York it’s actually required to do genetics counseling. It doesn’t have to be done with a genetics counselor, but that often works out best in my experience.

 There are federal protections. The Genetic Information Nondiscrimination Act of 2008 is designed to protect people from discrimination with regard to health insurance and employment. However, as Dr Brannagan just mentioned, it does not cover state-regulated programs for long-term disability, life insurance, or long-term care policies. It’s really important that people understand what rights they have and what rights are not protected before they get genetic testing, so I agree with you.

The variable penetrance of the disease is also an important issue. Just because you have a positive genetic test does not mean you will ever develop symptomatic hATTR [hereditary amyloidosis]. Somebody has to think that through too, before being tested.

Yeah, it sounds a little absurd, but perhaps some people wonder whether they were adopted because their parents never expressed disease. It could simply be either a lack of diagnostics or the penetrance was incomplete; you’re absolutely right.

Expert panelists provide recommendations for gene panel testing with genetic counseling for evaluation of patients with hereditary ATTR amyloidosis. 

Genetic Testing in hATTR Amyloidosis  

Dr Brannagan, let’s shift gears and talk about diagnostic testing and how you assess a patient who you think potentially may have peripheral neuropathy on the basis of hATTR [hereditary amyloidosis transthyretin]. Can you start us off with electromyography [EMG]?

Electromyography and nerve conductions are standard tests to confirm the presence of hATTR neuropathy as well as any other type of neuropathy. For hereditary TTR [transthyretin] amyloidosis, we’d be looking for signs of an axonal neuropathy. We also frequently assess for carpal tunnel for treatment reasons because carpal tunnel could be treated with wrist braces or surgery. We also would like to confirm the presence of a neuropathy to differentiate it from other symptoms. Not everybody with numbness has a peripheral neuropathy. You could have spinal problems, anxiety, multiple sclerosis, or many other problems. It’s also important to note that if somebody has an EMG or nerve conductions that do not show a polyneuropathy, it doesn’t mean that they don’t have a neuropathy. It just means that the large myelinated fibers that are measured in the muscles are normal. However, there could still be small fiber involvement; the pain and temperature fibers and the autonomic fibers.

That’s great. I appreciate you making that point. Dr Polydefkis, you run a lab that focuses on epidermal nerve fiber densities. Can you explain to us what the utility of that analysis is and how it complements electromyography?

As Dr Brannagan said, nerve conduction focuses on a subset of fibers, large myelinated fibers. Skin biopsy looks at small unmyelinated fibers, so together the 2 tests are complementary. Skin biopsy detects a loss of epidermal or small unmyelinated fibers, and that’s a hallmark of small fiber neuropathy typically associated with distal pain, burning, dysesthesias. Then the tissue can also be used to detect amyloid and additionally to gain some insight into sudomotor function and sweat function by looking at sweat gland innervation.

Great. Dr Polydefkis says that you can see amyloid on skin punch biopsies. Is that your experience, Dr Brannagan?

Yes, we’ve seen amyloid periodically from skin biopsies. We’ve also seen people who have confirmed hereditary TTR amyloid that the skin biopsy has been negative for amyloid. Dr Polydefkis doesn’t claim that it has 100% specificity, but it has been a useful test to document tissue deposition of amyloid.

Dr. Polydefkis, I neglected to ask you what the sensitivity of the skin punch biopsies are for demonstrating small fiber neuropathy.

For patients who are symptomatic with neuropathy, it’s on the order of 75%.

OK. Dr Dyck, first of all, do you use skin punch biopsies? I’ll have some questions about additional testing that you might have experience with.

We run a peripheral nerve pathology lab in which we process both cold nerves. We’re looking at large and small fibers, as well as epidermal nerve fiber density. We do our own lab as well for a skin biopsy.

Can you give us a little information about the utility of heart rate deep breathing or perhaps SUDOSCAN assessments?

At the Mayo Clinic, we are very spoiled in that we have more testing for small fibers than most places would have. We have autonomic reflex screens in which we can interrogate the autonomic nervous system and we can look at different components of that. We have thermoregulatory sweat tests, where we can paint patients from stem to stern, throw them in an oven and cook them, and see how they sweat; it gives us a good idea of what is happening to unmyelinated fibers. We have epidermal nerve fiber density testing that we can do. For that reason, we don’t actually use SUDOSCANs and things like that, because we have more sophisticated tests at interrogating small fiber function. The heart rate variability with deep breathing is part of the autonomic reflex screens. When we’re seeing patients, we’re doing the whole test and not just that. The problem we’ve had with that in the studies is that if patients have dysrhythmias, that part of the testing goes out the window. In fact, the inotersen trial used that as an end point. When Alnylam Pharmaceuticals Inc and patisiran came along, they just went to measuring orthostatic blood pressures so that they could look at all patients.

Dr Witteles, can you give us a little perspective on noninvasive diagnosis of TTR amyloid cardiomyopathy?

Sure. This has been 1 of the biggest factors that’s led to the explosion in diagnosis of TTR cardiomyopathy, which is because most patients can be diagnosed easily and noninvasively. It’s really a 2-step process. Step 1 is making sure that you don’t miss AL [light chain] amyloidosis. That’s done with blood and urine testing to rule out a monoclonal protein with the serum and urine protein electrophoresis with immunofixation and a serum-free light chain assay. Assuming there’s no evidence of a monoclonal protein, then you can move on to what sometimes is called bone scintigraphy or, in this country, technetium pyrophosphate, also known as PYP imaging which will typically show a characteristic pattern of uptake of the tracer in hearts infiltrated with TTR amyloid fibrils. In these days, that is how most patients are diagnosed, it’s an acceptable way of making a confirmative diagnosis and being able to start therapy. If there are any doubts or patients do have a monoclonal protein, then you need to go on to biopsy, and we can debate where the best spot is to biopsy in that case.

Diagnostic criteria commonly used to ensure an accurate diagnosis of hereditary ATTR amyloidosis is dissected. 

Diagnostic Strategies in hATTR Amyloidosis 

Dr Dyck, are diabetic disease and ATTR [amyloidosis transthyretin] neuropathy exclusive or can they be combined, and how do you differentiate?

He’s raised a very good point. In fact, I was going to take some issue with that. I don’t think we can just assume if you have a positive genetic test, then your neuropathy is due to hATTR [hereditary ATTR]. For example, I saw an African American gentleman who had a positive genetic test, who had been diabetic for 30 years, had some prickling in his toes, had a cardiomyopathy, and they were all ready to put him on either patisiran or inotersen, and they wanted me to start it. I looked at him, and his neuropathy was very minimal. He had background retinopathy, and he had background nephropathy. I did a nerve biopsy on him, and there was no amyloid. I determined his neuropathy was a diabetic polyneuropathy and not because of his hATTR. Now, his cardiologist and his hematologist may not have been thrilled with me, but I still think there is some intellectual honesty that we need to do.

A positive genetic test is not a diagnosis of hATTR. It confers a carrier state. The cardiologist and the neurologist have diverged in this respect, because a positive PYP [pyrophosphate] scan is taken as diagnostic evidence that you have an amyloid cardiomyopathy. From my perspective, you can have a neuropathy in a genetic test, but you still need to do some more work to establish that the 2 are related. I personally still prefer having a positive tissue diagnosis of amyloid for the neuropathy cases.

Panelists suggest how to differentiate between diabetic neuropathy and ATTR amyloidosis.  

P. James B. Dyck, MD

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P. James B. Dyck, MD

Articles

Future Treatment of hATTR Amyloidosis

Evaluating the Potential of Vultrisiran

Benefits of TTR Gene Silencers

Evaluating hATTR Amyloidosis Therapy

Recent Advances in hATTR Amyloidosis Treatment

Identification of the Amyloid Protein

Tissue Biopsies in hATTR Amyloidosis

Genetic Testing in hATTR Amyloidosis

Diagnostic Strategies in hATTR Amyloidosis

Diabetes and hATTR Amyloidosis Neuropathy

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