Distinct small-fiber dysfunction profiles in CMT1A and RFC1 disease: a multimodal study

Abstract Background Charcot-Marie-Tooth disease 1A (CMT1A) and Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS)/Replication Factor Complex subunit 1 (RFC1)-related disease affect large nerve fibers, but small fiber dysfunction may contribute to pain and dysautonomia. We applied a multimodal protocol, including potentials elicited by a micropatterned electrode targeting intraepidermal nerve endings, to characterize small fiber involvement. Methods In this cross-sectional study, healthy controls (HC) and patients with CMT1A or RFC1 disease underwent neurologic examination, autonomic assessment with the composite autonomic symptom score−31 (COMPASS-31) and compound autonomic dysfunction test (CADT), electrochemical skin conductance (ESC), nociceptive evoked potentials (NEPs), pain-related evoked potentials (PREPs), somatosensory evoked potentials (SEPs), and skin biopsy. Results Twenty-one patients with CMT1A, 16 with RFC1 disease, and 21 HC were included. Neuropathic pain occurred in 33% of CMT1A and 81% of RFC1 patients. Dysautonomia was prominent in RFC1 disease, with abnormal CADT scores in 94%, COMPASS-31 scores of 7–46, and abnormal ESC in 63%, compared with 24% in CMT1A. N40 NEP latencies were prolonged in both patient groups versus HC (p<0.001), with absent responses in 33% and 44%, respectively. PREPs showed prolonged N2 latencies in CMT1A (p=0.003), with absent N2 responses in 57%; in RFC1 disease, N2 responses were absent in 50%. Skin biopsy showed length-dependent intraepidermal nerve fiber density loss in CMT1A and severe non-length-dependent epidermal denervation in RFC1 disease. Discussion Multimodal assessment integrating ESC, NEPs, PREPs, and skin biopsy identifies distinct Aδ- and C-fiber dysfunction patterns in CMT1A and RFC1 disease and may support phenotyping and small-fiber biomarker development in peripheral neuropathies.