Abstract
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.
Introduction
Transthyretin amyloidosis (ATTR amyloidosis) is a progressive, multisystemic disease characterized by the accumulation of amyloid fibrils in various tissues and organs1,2. It manifests in two forms: hereditary transthyretin amyloidosis (ATTRv), which is inherited in an autosomal dominant manner, and acquired wild-type transthyretin amyloidosis (ATTRwt)3. ATTRv amyloidosis develops on the basis of a pathogenic variant in the transthyretin (TTR) gene, leading to transthyretin tetramer dissociation, misfolding of transthyretin monomers and formation of amyloid fibrils4. Currently, over 130 pathogenic variants of the TTR gene have been described5. Historically, ATTRv amyloidosis has been associated primarily with neurologic manifestations in the form of rapidly progressive sensorimotor and autonomic polyneuropathy in addition to cardiomyopathy, gastrointestinal, renal, or ocular disorders6. However, clinical manifestations vary considerably depending on the respective variant and other factors such as occurrence in an endemic vs. a non-endemic region3,7. Therefore, “red flag” symptom clusters with findings considered typical were defined to facilitate the diagnosis of ATTRv amyloidosis8.
In contrast to ATTRv amyloidosis, the pathophysiology of ATTRwt amyloidosis has been far less understood. ATTRwt amyloidosis typically occurs in the elderly population with a strong male-dominated gender distribution9. Since cardiomyopathy is often the most prominent symptom in ATTRwt amyloidosis, concomitant neuropathy has long been underdiagnosed10. However, recent studies have drawn attention to a higher-than-expected prevalence of neuropathy in ATTRwt patients and further characterized peripheral neuropathy in ATTRwt amyloidosis as predominantly mild10,11. Nevertheless, there are only limited data on the characterization of polyneuropathy in ATTRwt patients and comprehensive comparison of the features of neuropathy in ATTRv and ATTRwt amyloidosis.
Therefore, in this study we aimed to identify the prevalence as well as clinical and electrophysiological features of polyneuropathy in a mixed cohort of patients with hereditary and acquired transthyretin amyloidosis at first presentation at an interdisciplinary amyloidosis center in a non-endemic area.