Methods
Next-generation sequencing along with Sanger confirmation was performed for family members and healthy controls. LC-MS was used for lipidomic analysis in participants' plasma. Quantitative magnetic resonance imaging (qMRI) was performed to study sciatic nerve pathologies.
Objective
Sphingolipids are enriched in the nerves. Serine-palmitoyltransferase (SPT) catalyzes the key step of sphingolipids biosynthesis. Mutations in SPT subunits (SPTLC) lead to the excessive production of neurotoxic deoxysphingolipids (DoxSLs) in patients with Hereditary Sensory Neuropathy Type-1C (HSN1C). HSN1C is an autosomal dominant peripheral neuropathy characterized by sensory loss and distal muscle weakness. In this study, by leveraging a HSN1C family with a previously reported N177D mutation in SPTLC2, we aim to further define the spectrum of DoxSL species and the peripheral neve pathology of the disease.
Results
A heterozygous N177D mutation in SPTLC2 was co-segregated in individuals with sensory-motor deficits in the limbs. Nerve conduction studies (NCS) revealed nonuniform slowing of conduction velocities. In line with the NCS, qMRI detected a pattern of nerve changes similar to those in acquired demyelinating polyneuropathies. Additionally, we detected a significant increase in multiple species of deoxysphingoid bases and deoxyceramides in patients' plasma. Interpretation: Mutations in the SPTLC2 cause a demyelinating phenotype resembling those in acquired demyelinating polyneuropathy. The species of increased DoxSLs in HSN1C may be more diverse than originally thought.