Hereditary transthyretin amyloidosis (hATTR) with polyneuropathy is a rare, adult-onset, autosomal dominant disease characterized by amyloid deposits in the endoneurium and involvement of the peripheral nervous system that can be difficult to diagnose.
The misfolding and subsequent aggregation of TTR protein in the body is the key driver of this disease. hATTR with polyneuropathy is indicated by symptoms such as paresthesia, numbness, and pain. Autonomic dysfunction can give rise to symptoms such as poor digestion and sexual dysfunction. Patients may also present with sensory loss, primarily in the upper and lower limbs.
The global prevalence of this condition is roughly 1 per 1,000,000 persons, making it an exceedingly rare disorder. Nevertheless, it is considered endemic in a number of countries, such as Portugal, Japan, and Sweden. In these parts of the world, adequate investigations are typically carried out, leading to a higher rate of diagnosis. On the other hand, this disease is typically missed in parts of the world where the incidence is low.
“Multiple misdiagnoses before the correct diagnosis of amyloid neuropathy have been reported in 20–40% of cases,” according to Adams and colleagues in the Journal of Neurology.
When it comes to neuropathic disease, clinicians usually have a long list of potential differential diagnoses; hence, they are likely to misdiagnose this rare condition for something more common. According to Adams et al, this condition is most commonly misdiagnosed as chronic inflammatory demyelinating polyradiculoneuropathy, idiopathic axonal polyneuropathy, or diabetic neuropathy.
Neuropathy is difficult to treat unless the underlying pathophysiology is known; patients are therefore unlikely to recover unless a correct diagnosis of hATTR with polyneuropathy is made. In addition, a misdiagnosis means that amyloid deposits in various organs will continue to drive organ dysfunction, even if patients remain asymptomatic. For example, while the heart is usually involved, most patients are asymptomatic of heart disease; it is only when cardiac imaging is carried out that anomalies are discovered, such as cardiac hypertrophy.
When should clinical suspicion of this condition be raised? Adams and colleagues believe that suspicion should be high in elderly patients presenting with progressive, disabling polyneuropathy. Physicians should also pay special attention to patients who have neuropathy with signs of multisystemic involvement. In addition, a positive family history is always elucidating.
Read more about hATTR etiology
To confirm a clinical suspicion of hATTR with polyneuropathy, physicians can order DNA sequencing to confirm the specific amyloidogenic TTR variant. Second, clinicians may choose to perform a biopsy to test for the presence of amyloid deposition; common biopsy sites include the labial salivary gland, skin, nerve, and the submucosa of the gastrointestinal tract.
“Early and accurate diagnosis of ATTR amyloidosis allows early treatment and will potentially modify disease progression in patients,” Adams et al conclude.
Follow-up After Diagnosis
Upon confirmation, patients should be clinically examined every 3 to 6 months to monitor disease progression. All symptoms initially presented should be re-examined to establish whether they have worsened. An adequate neurological examination should include functional scores (such as walking ability) and an assessment of autonomic function (such as the presence of gastrointestinal disturbances and erectile dysfunction).
In hATTR, physicians should place a high importance on the continued appraisal of cardiac parameters. At a minimum, this should include electrocardiography and echocardiography. In addition, the cardiac biomarker N-terminal prohormone of brain natriuretic peptide (NT-proBNP) can yield important information regarding the state of a patient’s cardiac health.
It is also advisable for physicians to perform periodic ophthalmology assessments and measure a patient’s body mass index. Some studies recommend that additional assessments, such as nerve conduction studies, manual grip strength, and lower limb function, be carried out. However, because these tests have only been carried out in small studies, their usefulness has yet to be validated in a large cohort of patients.
In the International Journal of General Medicine, Vélez-Santamaría and colleagues discuss the various therapies available to treat hATTR with polyneuropathy.
The first is a liver transplant, which works by replacing the main source of mutant TTR. A healthy liver produces wild-type TTR, which is more stable and less amyloidogenic. Studies indicate that a liver transplant can extend survival, although neuropathy and cardiomyopathy may persist.
Two interesting groups of therapies have emerged over the last few years: TTR silencers and TTR stabilizers. TTR silencers such as patisiran are small interfering RNAs (siRNAs) that trigger silencing complexes that bind to their complementary mRNA. Although studies indicate that TTR silencers can ameliorate neuropathy, disability/mortality risk remains high if the drug is only administered at a late stage of the disease.
TTR stabilizers such as tafamidis work by inhibiting the first dissociation step of the amyloidogenic cascade. Studies demonstrate that TTR stabilizers can improve neurological function and nutritional status and lower decline in functional capacity and quality of life.
Read more about hATTR treatment
While it is important that physicians use the right management tools to treat hATTR with polyneuropathy, it is vital that disease progression is closely monitored, given the absence of a definite cure. By tracking disease progression, physicians can adapt their prescribed treatment regimens accordingly, securing quality of life and possibly improving life expectancy.
“[hATTR with polyneuropathy] is a progressive and lethal disease in which early therapeutic intervention is key for better patient outcomes,” Vélez-Santamaría and colleagues conclude. “To monitor the disease course, clinicians should undertake detailed assessments of the multiple symptoms and signs of neuropathy at baseline and during follow-up.”
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
Vélez-Santamaría V, Nedkova-Hristova V, Morales de la Prida M, Casasnovas C. Hereditary transthyretin amyloidosis with polyneuropathy: monitoring and management. Int J Gen Med. 2022;15:8677-8684. doi:10.2147/IJGM.S338430