Blood 1‐Deoxysphingolipid Levels Are Associated With Epidermal Denervation in Small Fiber Neuropathy

Background and Aims Dysfunctional sphingolipid metabolism leads to nerve fiber degeneration, particularly of small caliber Aδ and C fibers, in hereditary sensory and autonomic neuropathies. We aimed to investigate the association of blood 1‐deoxysphingolipid (1‐deoxySL) profiles and skin denervation in idiopathic small fiber neuropathy (SFN). Methods Seventy‐five patients with idiopathic SFN were recruited prospectively. Patients underwent a skin punch biopsy at the lower leg and upper thigh for intraepidermal nerve fiber density (IENFD) quantification. IENFD was correlated with individual blood 1‐deoxySL levels, amino acid profiles, and determinants of glucose and lipoprotein metabolism. Results Median distal IENFD in SFN patients was 5.3 fibers/mm. In 38/75 (51%) patients, IENFD was ≤ 5.3 fibers/mm (i.e., “low fiber density,” LFD), while in 37/75 (49%) patients, IENFD was > 5.3 fibers/mm (i.e., “high fiber density,” HFD). 1‐deoxySL was higher in patients with LFD compared to HFD ( p < 0.05). Fasting plasma glucose was also higher in patients with LFD than in patients with HFD ( p < 0.01), while HDL was lower in patients with LFD compared to HFD ( p < 0.001). Interpretation 1‐deoxySL, lipoprotein metabolism, and glucose levels are associated with the extent of epidermal denervation in SFN, supporting the role of this metabolic axis in small nerve fiber pathology.