Polyneuropathy in hereditary and wildtype transthyretin amyloidosis, comparison of key clinical features and red flags.

Transthyretin (TTR) amyloidosis manifests in two distinct forms: hereditary (ATTRv) and wild-type transthyretin amyloidosis (ATTRwt). Despite being one of the commonest manifestations in ATTRv amyloidosis, the presence of polyneuropathy has long been underestimated in ATTRwt patients. This prospective study enrolled 72 patients with ATTRv (n = 11) and ATTRwt (n = 61) amyloidosis. Our standardized protocol included a detailed patient history, clinical and electrophysiological examinations, assessment of unrelated neuropathy risk factors and predefined red flags for ATTRv amyloidosis, as well as serum neurofilament light chain concentrations (NfL). We found signs of polyneuropathy in all ATTRv patients and a vast majority of ATTRwt patients (84%). Predefined red flag symptom clusters were prevalent in both subgroups, indicating significant overlap, however gastrointestinal symptoms were more frequent in ATTRv amyloidosis (p = 0.008), while carpal tunnel syndrome was less common (p = 0.015) compared to ATTRwt amyloidosis. The groups differed in severity of polyneuropathy, with ATTRv patients demonstrating more pronounced subjective limitations, greater clinical disability, marked nerve conduction abnormalities, and higher serum NfL concentrations (p = 0.011). Our findings underscore a high prevalence of polyneuropathy in patients with transthyretin amyloidosis, irrespective of its origin. Differences in the severity of polyneuropathy as well as in red flags indicate different underlying mechanisms of damage.