Skin nerve pathology: Biomarkers of premanifest and manifest amyloid neuropathy

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 multivariate 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.

hATTR Pathology: Nerve Biopsy Results from Italian Referral Centers

“…Considering unmyelinated fibers, electron microscope examination, performed in half of the biopsies, also confirmed their involvement in late-onset hATTR, as demonstrated by other techniques [33][34][35].…”

Diagnostic criteria for small fibre neuropathy in clinical practice and research

“…The assessment of small fibre nerves should be in the frame of a well-defined clinical context (Cazzato and Lauria, 2017). The early diagnosis of SFN is important to identify patients at risk of developing more generalized neuropathy such as that associated with amyloidosis (Chao et al , 2019) and diabetes (Lauria et al , 2003; Devigili et al , 2008; Khoshnoodi et al , 2016; Loseth et al , 2016). The recent identification of sodium channel gene mutations in idiopathic and diabetic SFN patients (Huang et al , 2014; Waxman et al , 2014; Alsaloum et al , 2019; Eijkenboom et al , 2019 a ) has enlarged the spectrum of neuropathic pain disorders including new phenotypes (Faber et al , 2012 a , b ; Hoeijmakers et al , 2012; Bennett and Woods, 2014; Devigili et al , 2014; Serra et al , 2014; Doppler et al , 2015; Martinelli-Boneschi et al , 2017), allowing the development of new innovative in vitro (Persson et al , 2013; Rolyan et al , 2016) and in vivo (Eijkenboom et al , 2019 b ) models, and has prompted randomized clinical trials with new targeted compounds.…”

Peripheral neuropathy symptoms in wild type transthyretin amyloidosis

“…We also describe that three of our patients of group B had reduced epidermal nerve fiber density on skin biopsy, but we were unable to find amyloid deposits on the skin biopsy. Prior studies 25,26 performed in patients with hereditary ATTR show that amyloid deposits in the skin are more prevalent in patients with increasing FAP stage score. Patients with small fiber neuropathy, as in our study, would fall in FAP stage score 1, when amyloid deposits are rarely seen but decreased epidermal nerve fiber density is already noticeable.…”