SFN constitute a dreadful disease mainly characterized by neuropathic pain and autonomic dysfunction. Despite extensive diagnostic procedures, the underlying mechanisms remain unclear in many affected individuals. 1-deoxy-sphingoid bases, derived from L-alanine instead of L-serine, are neurotoxic due to disturbances of axonal outgrowth.

We characterized 100 patients (f:m=70:30; mean age: 44.8years) with a histologically confirmed, idiopathic SFN. Phenotypes were assessed by a detailed symptom history and pain questionnaires, a neurological examination, and quantitative sensory testing (QST) following the protocol of the German Research Network for Neuropathic Pain. A large fiber polyneuropathy was excluded by sensory and motor nerve conduction studies of the lower limbs. The amino acid and sphingolipid profiles were assessed in plasma and correlated with clinical phenotypes. Pathogenetic variants in SPTLC1 and SPTLC2 were excluded in all cases.

Neurotoxic 1-deoxy-sphingoid bases correlated with the histological severity of nerve fiber degeneration, but not with Aδ and C fiber dysfunction in the QST. They were associated with lower L-serine levels in plasma and with different features of the metabolic syndrome. We conclude that arterial hypertension, obesity, and dyslipidemia are risk factors for the development of SFN, even in the absence of diabetes mellitus. 1-deoxy-sphingolipids might be a common link to nerve fiber degeneration.