Intraepidermal nerve fibre density as biomarker in Charcot–Marie–Tooth disease type 1A

Abstract

Charcot–Marie–Tooth disease type 1A, caused by a duplication of the gene peripheral myelin protein 22 kDa, is the most frequent subtype of hereditary peripheral neuropathy with an estimated prevalence of 1:5000. Patients suffer from sensory deficits, muscle weakness and foot deformities. There is no treatment approved for this disease. Outcome measures in clinical trials were based mainly on clinical features but did not evaluate the actual nerve damage. In our case–control study, we aimed to provide objective and reproducible outcome measures for future clinical trials. We collected skin samples from 48 patients with Charcot–Marie–Tooth type 1A, 7 patients with chronic inflammatory demyelinating polyneuropathy, 16 patients with small fibre neuropathy and 45 healthy controls. To analyse skin innervation, 40-µm cryosections of glabrous skin taken from the lateral index finger were double-labelled by immunofluorescence. The disease severity of patients with Charcot–Marie–Tooth type 1A was assessed by the Charcot–Marie–Tooth neuropathy version 2 score, which ranged from 3 (mild) to 27 (severe) and correlated with age (P < 0.01, R = 0.4). Intraepidermal nerve fibre density was reduced in patients with Charcot–Marie–Tooth type 1A compared with the healthy control group (P < 0.01) and negatively correlated with disease severity (P < 0.05, R = −0.293). Meissner corpuscle (MC) density correlated negatively with age in patients with Charcot–Marie–Tooth type 1A (P < 0.01, R = −0.45) but not in healthy controls (P = 0.07, R = 0.28). The density of Merkel cells was reduced in patients with Charcot–Marie–Tooth type 1A compared with healthy controls (P < 0.05). Furthermore, in patients with Charcot–Marie–Tooth type 1A, the fraction of denervated Merkel cells was highly increased and correlated with age (P < 0.05, R = 0.37). Analysis of nodes of Ranvier revealed shortened paranodes and a reduced fraction of long nodes in patients compared with healthy controls (both P < 0.001). Langerhans cell density was increased in chronic inflammatory demyelinating polyneuropathy, but not different in Charcot–Marie–Tooth type 1A compared with healthy controls. Our data suggest that intraepidermal nerve fibre density might be used as an outcome measure in Charcot–Marie–Tooth type 1A disease, as it correlates with disease severity. The densities of Meissner corpuscles and Merkel cells might be an additional tool for the evaluation of the disease progression. Analysis of follow-up biopsies will clarify the effects of Charcot–Marie–Tooth type 1A disease progression on cutaneous innervation.

Subepidermal Schwann cell counts correlate with skin innervation – an exploratory study

“…The assessment of IENFD revealed two patient subgroups: 15 patients had a normal distal IENFD (median 8 [range, [6][7][8][9][10][11][12][13] fibers/mm) and 13 patients had reduced distal IENFD (median, 4 [range, 1-5] fibers/mm; Figure 3A). Healthy controls had normal distal IENFD (median, 9 [range, [6][7][8][9][10][11][12][13][14][15][16][17][18] fibers/mm). We compared the parameters determined between these two patient groups and with healthy controls and found lower numbers of solitary Schwann cells per millimeter in SFN patients with reduced IENFD vs those with normal IENFD (Figure 3B).…”

Transient hypoalgesia after COVID-19 infection

“…Specimens were processed for the assessment of skin innervation following standardized rules and as previously reported. 1 , 2 Additional stains included immunofluorescence for transient receptor potential vanilloid 1 (TRPV1) (ACC-030 rabbit polyclonal antibody; Alomone Labs, Jerusalem, Israel) and CGRP (ab135271 rabbit polyclonal antibody; abcam, Cambridge, United Kingdom) with appropriate secondary antibodies.…”

Studying human nociceptors: from fundamentals to clinic

“…Clinically, the intraepidermal nerve fibre density (IENFD), a measure of individual small fibre terminals per area, can be used to monitor nociceptor density through minimally-invasive skin biopsy 23 and decreased IENFD was developed as a diagnostic measure particularly in small fibre neuropathy. 24 , 25 Decreased IENFD has been demonstrated in many painful conditions and diseases including diabetic polyneuropathy, 26 , 27 carpal tunnel syndrome (nerve entrapment), 28 Charcot-Marie-Tooth disease type 1A, 29 chronic ischaemic pain, 30 complex regional pain syndrome, 31 Guillain-Barré syndrome, 32 Fabry disease, 33 and more (for a review see Sommer and Lauria 34 ) ( Fig. 1 ).…”