Red flags typically associated with polyneuropathy in hereditary transthyretin amyloidosis (hATTR) are highly useful in differentiating this disorder from chronic idiopathic axonal polyneuropathy (CIAP), according to a study published in Neurological Sciences. 

hATTR is a condition in which misfolded TTR protein aggregates and deposits across multiple organs, often leading to complications such as peripheral neuropathy. Treatment is most effective when initiated during the early stages of the disease; however, diagnosis is often hampered by phenotypic heterogeneity. 

No underlying etiology can be found in many patients presenting with polyneuropathy, even after an extensive diagnostic workup process. Some have proposed routine genetic testing in patients with polyneuropathy of an unknown origin as a possible solution to this problem; however, previous studies on the role of genetic testing in discerning underlying etiology have been mixed. More specifically, genetic testing has often confounded hATTR-associated polyneuropathy with CIAP. 

The authors of this study sought to further investigate the merits of TTR gene sequencing in a population of patients with polyneuropathy. At their hospital, 338 patients with chronic polyneuropathy underwent TTR gene sequencing between January 2009 and January 2020. The research team wanted to identify the clinical features of patients with either hATTR-associated polyneuropathy or CIAP at first presentation. They also investigated if any patients with hATTR-associated polyneuropathy were misdiagnosed as having CIAP via genetic studies. 

Read more about hATTR etiology 

The research team were also assessing whether the presence of previously recognized red flags for hATTR-associated polyneuropathy (such as a positive family history, cardiac signs suggestive of hATTR, rapid symptomatic progression, neuropathic pain, walking disability within the first 5 years, and autonomic symptoms, among others) were useful in raising the suspicion index for diagnosing this disorder. 

The researchers reported that the yield of TTR gene sequencing among the 338 patients with chronic polyneuropathy was a mere 3%. In addition, it did not adequately identify patients with hATTR-associated polyneuropathy who had a clinical presentation typical of CIAP. Thus, they concluded that routine genetic testing in this group of patients was not useful. However, the authors found that a thorough assessment of red flags for hATTR-associated polyneuropathy in patients with chronic polyneuropathy of unknown etiology was “paramount” in raising the suspicion index for this disorder.

In conclusion, red flag symptoms are more useful than genetic testing in differentiating hATTR-associated polyneuropathy from CIAP. 


Warendorf JK, van der Star GM, Dooijes D, Notermans NC, Vrancken AFJE. Red flags and adjusted suspicion index for distinguishing hereditary transthyretin amyloid polyneuropathy from idiopathic axonal polyneuropathyNeurol Sci. Published online June 2, 2023. doi:10.1007/s10072-023-06859-w