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.