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Serine\u2010palmitoyltransferase (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\u20101C (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 <jats:italic>SPTLC2<\/jats:italic>, we aim to further define the spectrum of DoxSL species and the peripheral neve pathology of the disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Next\u2010generation sequencing along with Sanger confirmation was performed for family members and healthy controls. LC\u2010MS was used for lipidomic analysis in participants\u2019 plasma. Quantitative magnetic resonance imaging (qMRI) was performed to study sciatic nerve pathologies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A heterozygous N177D mutation in <jats:italic>SPTLC2<\/jats:italic> was co\u2010segregated in individuals with sensory\u2010motor 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\u2019 plasma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Mutations in the <jats:italic>SPTLC2<\/jats:italic> cause a demyelinating phenotype resembling those in acquired demyelinating polyneuropathy. The species of increased DoxSLs in HSN1C may be more diverse than originally thought.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51110","type":"journal-article","created":{"date-parts":[[2020,7,31]],"date-time":"2020-07-31T03:55:24Z","timestamp":1596167724000},"page":"1502-1512","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Demyelination in hereditary sensory neuropathy type\u20101C"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0250-7342","authenticated-orcid":false,"given":"Sadaf","family":"Saba","sequence":"first","affiliation":[{"name":"Center for Molecular Medicine and Genetics Wayne State University School of Medicine Detroit Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongsheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology Wayne State University School of Medicine Detroit Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna Rao","family":"Maddipati","sequence":"additional","affiliation":[{"name":"Lipidomics Core Facility, Department of Pathology Wayne State University School of Medicine Detroit Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melody","family":"Hackett","sequence":"additional","affiliation":[{"name":"Department of Neurology Wayne State University School of Medicine Detroit Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Neurology Wayne State University School of Medicine Detroit Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine and Genetics Wayne State University School of Medicine Detroit Michigan"},{"name":"Department of Neurology Wayne State University School of Medicine Detroit Michigan"},{"name":"Department of Biochemistry, Microbiology and Immunology Wayne State University School of Medicine Detroit Michigan"},{"name":"John D. 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