Abstract

Objective

Small‐fiber sensory and autonomic symptoms are early presentations of familial amyloid polyneuropathy (FAP) with transthyretin (TTR) mutations. This study aimed to explore the potential of skin nerve pathologies as early and disease‐progression biomarkers and their relationship with skin amyloid deposits.

Methods

Skin biopsies were performed in patients and carriers to measure intraepidermal nerve fiber (IENF) density, sweat gland innervation index of structural protein gene product 9.5 [SGII(PGP9.5)] and peptidergic vasoactive intestinal peptide [SGII(VIP)], and cutaneous amyloid index. These skin pathologies were analyzed with clinical disability assessed by FAP stage score (stage 0~4) and compared to neurophysiological and psychophysical tests.

Results

There were 70 TTR‐mutant subjects (22 carriers and 48 patients) and 66 cases were TTR‐A97S. Skin nerve pathologies were distinct according to stage. In carriers, both skin denervation and peptidergic sudomotor denervation were evident: (1) IENF density was gradually reduced from stage 0 through 4, and (2) SGII(VIP) was markedly reduced from stage 1 to 2. In contrast, SGII(PGP9.5) was similar between carriers and controls, but it declined in patients from stage 2. Skin amyloids were absent in carriers and became detectable from stage 1. Cutaneous amyloid index was correlated with SGII(PGP9.5) and stage in a multivariable mixed‐effect model. When all tests were compared, only IENF density, SGII(PGP9.5), and cutaneous amyloid index were correlated with stage, and IENF density had the highest abnormal rate in carriers.

Interpretation

Biomarkers of sensory and sudomotor innervation exhibited a stage‐dependent progression pattern, with sensory nerve degeneration as the early skin nerve pathology.

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