P. James Dyck, MD, on Research Advances in Hereditary Transthyretin Amyloidosis
Hereditary transthyretin amyloidosis (hATTR), a progressive disease involving the buildup of amyloid fibril deposits in organs and tissues throughout the body, has an estimated global prevalence of 50,000 people.1 Because hATTR leads to significant morbidity and mortality, prompt diagnosis and treatment are paramount.1
At the American Neurological Association’s 145th Annual Meeting, P. James Dyck, MD, gave a talk on recent research and treatment advances for hATTR with polyneuropathy.2 After Dr Dyck’s presentation, Neurology Learning Network caught up with him about the key advances in this area.
Dr Dyck is a consultant in the Department of Neurology and a professor of neurology at Mayo Clinic in Rochester, Minnesota.
Neurology Learning Network: What have been some key recent research advances in the pathogenesis, clinical care, and features of hATTR?
Dr Dyck: I think the biggest recent advances in hATTR are the clinical trials. This is a disease which has, up to this time, been poorly treated. The treatments have historically consisted of liver transplantation, and over the last several years, we have shown that both membrane stabilizers—diflunisal and tafamidis—and gene‑silencing drugs—patisiran and inotersen—have changed the course of this disease. These are drugs that have saved people's lives. Two large, multicenter studies on hATTR with gene‑silencing drugs have been home runs, so to speak, and they have changed the course of the disease for the patients who have it. These are very exciting times for people with hATTR.
NLN: Could you discuss the effects of amyloidosis on peripheral neuropathy?
Dr Dyck: In the peripheral nerve, it is not clear what about amyloidosis causes a neuropathy. It is actually a fundamentally important question that we have not answered. That will require further research and understanding. Early on, hATTR amyloidosis presents as a very nondescript peripheral neuropathy. As it progresses, there are certain features that are major clues to hATTR amyloidosis. Patients with hATTR amyloidosis have often severe autonomic neuropathy, orthostasis, lightheadedness, sexual dysfunction, gastric dysmotility, cachexia, pain, and sensory neuropathies. A combination of weakness, sensory loss, and larger autonomic neuropathy are clues for either AL neuropathy or TTR amyloid neuropathy.
There are also comorbid conditions that are often clues, such as carpal tunnel syndrome occurring with the neuropathy. Lumbar spinal stenosis has been associated with TTR amyloid neuropathy. A coexisting cardiomyopathy is another key clue for a TTR amyloid neuropathy. Neurologists should keep all of these clues for hATTR in mind when they see patients.
NLN: Could you discuss the recently approved molecular therapies for this patient population, as well as any treatments on the horizon?
Dr Dyck: As I mentioned earlier, we have treatments available here and now. Patisiran and inotersen are gene‑silencing drugs that are approved and are being used for the treatment of TTR amyloid neuropathy. There are ongoing trials for other agents and for different variations of these drugs, so they can be given less frequently and subcutaneously. I think these are very exciting times in research.
NLN: What key takeaways on these topics do you hope to leave with neurologists and neurology providers?
Dr Dyck: The take‑home message for hATTR is that these are exciting times. In the past, treatments have been very limited. They consisted primarily of liver transplantation, which did work very well. Now, we have gene‑silencing drugs that can alter the long-term outcome of these patients and save lives.
We must perform genetic testing much more broadly than we have been in order to examine patients for mutations in hATTR. Wild‑type hATTR causes a cardiomyopathy. Rarely can it cause a peripheral neuropathy. Most of the patients with a neuropathy have mutant hATTR. Performing genetic testing will identify a carrier status. However, this does not prove that the neuropathy is caused by this.
Personally, I am still an old‑fashioned doctor, and I believe that amyloid is a tissue diagnosis. The tissues that you pursue include many different tissues of fat aspirates, a lip biopsy, a muscle biopsy, a rectal biopsy, and a peripheral nerve biopsy. I read peripheral nerve biopsies myself, and I still think there is a place for performing biopsies in these patients. We need to consider this condition much more commonly because treatments are now available.
- Gertz MA. Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. Am J Manag Care. 2017;23:S0. https://www.ajmc.com/view/hereditary-attr-amyloidosis-burden-of-illness-and-diagnostic-challenges-article
- Dyck J. Recent advances in amyloidosis: a disease you can't afford to miss. Amyloid polyneuropathy. Talk presented at: American Neurological Association 2020 Virtual Meeting; October 4-9, 2020. https://2020.myana.org/program/sessions/recent-advances-amyloidosis-disease-you-cant-afford-miss