Small nerve fiber involvement in CMT1A

Abstract

Objective: To assess the involvement of small nerve fibers in Charcot-Marie-Tooth type 1A (CMT1A).

Methods: We used indirect immunofluorescence and confocal microscopy on punch biopsies from glabrous (fingertip) and hairy (thigh and leg) skin of 20 unrelated patients with CMT1A to quantify somatic and autonomic nerve fibers. In particular, we quantified epidermal nerve fibers (ENF), Meissner corpuscles (MC), intrapapillary myelinated endings (IME), and sudomotor nerves. We correlated morphologic data with findings from quantitative sensory testing, sudomotor output, sympathetic skin response, and cardiovascular reflexes. A control population of healthy age- and sex-matched controls was included with a matching ratio of 1:2.

Results: We found a length-dependent loss of ENFs that worsened with aging. We also observed a loss of MCs, IMEs, and sudomotor nerves. The loss of ENF at distal leg correlated with the increase in heat-pain thresholds (p < 0.05) and with tactile thresholds (p < 0.05). Sudomotor nerve fiber loss correlated with ENF density (p < 0.05) and sweating output (p < 0.001).

Conclusions: We demonstrated through morphologic, physical, and psychophysical testing that small somatic and autonomic fibers are abnormal and cause symptoms in patients with CMT1A. Awareness of such symptoms by the clinician could lead to better treatment.

Figure 1. Somatic denervation in glabrous and hairy skin

Digital images from fingertip (A, B), thigh (C, D), and leg (E, F) show epidermal and dermal denervation in patients with Charcot-Marie-Tooth type 1A (CMT1A). A moderate length-dependent loss of epidermal nerve fibers is present in patients with CMT1A compared to controls (B, D, F compared to A, C, E). Morphologic abnormalities (arrowhead) and loss of Meissner corpuscles and intrapapillary myelinated endings are also evident in B. In addition to degenerative signs, frequent aspects of nerve remodeling (clusters) are observed (arrowheads in D and F). Scale bar: 100 µm. COLIV = collagen IV; MBP = myelin basic protein; PGP = protein gene product.

Figure 2. Cutaneous autonomic denervation

Confocal images show, in patients compared to controls, loss of cholinergic (vasoactive intestinal peptide [VIP]) sudomotor nerves (B compared to A) and loss of cholinergic and noradrenergic fibers in arteriovenous anastomoses (D compared to C) and arrector pili muscle (F compared to E). Scale bar: 100 µm.