Hereditary transthyretin amyloidosis (hATTR) is “a life-threatening, multisystem disease with a great variability in clinical presentation and course, and death within 10 years on average,” Luigetti and colleagues wrote in Therapeutics and Clinical Risk Management.
The disease is caused by mutations in the transthyretin gene which manifest as peripheral nervous system damage, both somatic and autonomic. The main driver of pathology in hATTR is the extracellular deposition of amyloid fibrils in various organs. Damage can also go beyond the nervous system, involving organs such as the heart, kidneys, and eyes.
Due to the poor prognosis of this disease, improving patients’ quality of life carries great importance. This means tackling the main systems that are affected and ensuring that critical biological processes are protected.
One manifestation of hATTR is polyneuropathy In the Journal of Neurology, Adams and colleagues conducted a review into ways in which the diagnosis of hATTR with polyneuropathy can be improved.
Multiple Diagnostic Challenges
“The diagnosis of this rare disease is a challenge for the neurologist and is most often delayed by 3–4 years, which impacts patients’ functional and vital prognosis,” Adams et al wrote.
These can be due to a number of reasons. For example, some patients experience a sporadic, late-onset form of the disease that is highly variable in how it presents itself. If a patient presents with polyneuropathy as an initial symptom, it is unlikely that hATTR would be considered in the beginning (physicians are obliged to rule out diabetic neuropathy, which is much more common).
Adams and colleagues pointed out that hATTR is considered endemic in some areas, such as Japan, Portugal, Brazil, and Sweden. In these countries, penetrance can be highly variable; in Portugal, 80% of mutation carriers exhibit symptoms by the age of 50 years; in Sweden, the figure is 11%.
“In these areas, the disease may not be as difficult to diagnose because it is aided by positive family history, high penetrance, and typical clinical presentation and by genetic counseling for, detection in, and follow-up of carriers of the mutant TTR gene,” Adams and colleagues wrote.
Read more about hATTR epidemiology
In nonendemic areas, epidemiological studies indicate this diagnosis is often missed altogether. In approximately 20% to 40% of cases, multiple misdiagnoses occur before a correct diagnosis is made.
There are some typical symptoms of hATTR with polyneuropathy: pain, paresthesia, numbness in the lower extremities, autonomic dysfunction, erectile dysfunction, fatigue, and weight loss. Sensory loss tends to start in the lower extremities and move toward the upper extremities. Patients with advanced disease may lose their motor skills and reflexes.
Physicians, especially when given limited time to interview and examine patients during initial primary care consultations, must be equipped with the knowledge of when to suspect hATTR.
“Suspicion of [hereditary transthyretin] amyloidosis should be high for patients with progressive and disabling polyneuropathy, particularly in elderly patients,” Adams and colleagues wrote. “The disease should also be considered in patients with neuropathy plus at least one red flag symptom suggestive of multisystemic involvement.”
Treating the Full Range of Symptoms
Because hATTR is a multisystem disease, an adequate medical response will require no less than a multidisciplinary approach.
First: the essentials. Anti-amyloid therapy should be commenced. This is to inhibit further production and aggregation of amyloid deposits. A multidisciplinary team should be able to identify any cardiac, renal, and ocular involvement and treat identified pathology accordingly.
One class of drugs that have been particularly useful in treating hATTR is transthyretin stabilizers, which act on circulating forms of transthyretin. Tafadimis, for example, is an oral, kinetic transthyretin stabilizer that results in transthyretin stabilization in 90% of patients.
Another class of medications that has shown promise is gene-silencing therapies. These therapies aim to decrease transthyretin hepatic production by targeting its mRNA. Studies have shown that this can significantly decrease transthyretin deposits in peripheral tissues.
With regard to the future of hATTR care, Luigetti and colleagues wrote, “The future challenges will be to find an effective therapy in patients with an advanced disease, and to assess the effects of amyloid deposit clearance with monoclonal antibodies, the potential of curative gene replacement therapy, and the potential benefit of combined therapies with a different mechanism of action, as well as the effects of disease-modifying therapies in presymptomatic individuals.”
Adams D, Ando Y, Beirão JM, et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol. 2021;268(6):2109-2122. doi:10.1007/s00415-019-09688-0
Luigetti M, Romano A, Di Paolantonio A, Bisogni G, Sabatelli M. Diagnosis and treatment of hereditary transthyretin amyloidosis (hATTR) polyneuropathy: current perspectives on improving patient care. Ther Clin Risk Manag. 2020;16:109-123. doi:10.2147/TCRM.S219979