Cutaneous nerve biomarkers in transthyretin familial amyloid polyneuropathy

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Transthyretin (TTR)‐mediated amyloidosis is an inherited, progressive, fatal disease caused by mutations in the TTR gene.1 TTR is a 55kD protein that transports thyroxine and retinol‐binding protein in the blood and cerebrospinal fluid (CSF) and normally exists as a tetramer. Mutations in TTR can lead to misfolding, resulting in aggregation and amyloid formation that infiltrate and damage affected tissues, primarily peripheral nerve and heart, resulting in TTR familial amyloidotic polyneuropathy (FAP) and familial amyloidotic cardiomyopathy.2 TTR‐FAP is a progressive, disabling neuropathy affecting the autonomic, sensory, and motor components of the peripheral nerve system.5 Classical symptoms of TTR‐FAP occur symmetrically in the distal lower extremities with tingling and prickly burning sensations of pain, suggesting early injury of small nerve fibers.1 Sural nerve biopsies have shown endoneurial amyloid deposits and small‐fiber reduction in TTR‐FAP,1 but the procedure is invasive and the multifocal patchy distribution of amyloid is a limiting factor. Early diagnosis is rare without a family history, and presentation is often misinterpreted as an idiopathic small‐fiber neuropathy. Additionally, there are reports of misdiagnosing cases as chronic inflammatory demyelinating polyradiculoneuropathy.8 As treatments for TTR‐FAP emerge, there is growing interest in diagnosing TTR‐FAP early, with the hope of slowing progression.
Previous work suggests that reductions in corneal nerves are associated with Neuropathy Impairment Score (NIS), intraepidermal nerve fiber density (IENFD), and Overall Neuropathy Limitations Scale9 in TTR‐FAP patients, whereas skin biopsies from patients with Ala97Ser TTR‐FAP demonstrated a severe distal leg IENFD reduction that correlated with CSF protein elevations.10 Other studies demonstrated that amyloid was present at low levels in the skin of patients with Ala97Ser TTR‐FAP, primarily within dermal blood vessels, but not within dermal collagen or arrector pili and sweat glands.11 In this study, we assessed whether skin biopsies can detect amyloid deposition in patients with known pathogenic TTR variants, with or without peripheral neuropathy, as well as patients with light‐chain (AL) amyloid. Among TTR patients, innervation of the epidermis, sweat glands, and arrector pili and the amount of amyloid (amyloid burden) present in 3mm skin biopsies from the proximal and distal leg were measured. Our results suggest that skin biopsy has promise to diagnosis amyloid early in the course of disease and that amyloid burden may serve as a biomarker for disease severity and progression.

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