title: The Variant p.(Arg183Trp) in SPTLC2 Causes Late-Onset Hereditary Sensory Neuropathy.
abstract: Hereditary sensory and autonomic neuropathy 1 (HSAN1) is an autosomal dominant disorder that can be caused by variants in SPTLC1 or SPTLC2, encoding subunits of serine palmitoyl-CoA transferase. Disease variants alter the enzyme's substrate specificity and lead to accumulation of neurotoxic 1-deoxysphingolipids. We describe two families with autosomal dominant HSAN1C caused by a new variant in SPTLC2, c.547C>T, p.(Arg183Trp). The variant changed a conserved amino acid and was not found in public variant databases. All patients had a relatively mild progressive distal sensory impairment, with onset after age 50. Small fibers were affected early, leading to abnormalities on quantitative sensory testing. Sural biopsy revealed a severe chronic axonal neuropathy with subtotal loss of myelinated axons, relatively preserved number of non-myelinated fibers and no signs for regeneration. Skin biopsy with PGP9.5 labeling showed lack of intraepidermal nerve endings early in the disease. Motor manifestations developed later in the disease course, but there was no evidence of autonomic involvement. Patients had elevated serum 1-deoxysphingolipids, and the variant protein produced elevated amounts of 1-deoxysphingolipids in vitro, which proved the pathogenicity of the variant. Our results expand the genetic spectrum of HSAN1C and provide further detail about the clinical characteristics. Sequencing of SPTLC2 should be considered in all patients presenting with mild late-onset sensory-predominant small or large fiber neuropathy.
authors.affiliation: Institute for Clinical Chemistry, University Hospital Zurich, University of Zurich, Zurich, Switzerland.|Competence Center for Personalized Medicine (CC-PM), Zurich, Switzerland.
authors.forename: Saranya
authors.initials: S
authors.lastname: Suriyanarayanan
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland.|Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Mari
authors.initials: M
authors.lastname: Auranen
authors.affiliation: Department of Clinical Neurophysiology, Medical Imaging Center, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Jussi
authors.initials: J
authors.lastname: Toppila
authors.affiliation: Department of Pathology, HUSLAB, University of Helsinki, Helsinki, Finland.
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Shcherbii
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland.
authors.forename: Eino
authors.initials: E
authors.lastname: Palin
authors.affiliation: Institute for Clinical Chemistry, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Neurocenter, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Tarja
authors.initials: T
authors.lastname: Lohioja
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Schlotter-Weigel
authors.affiliation: Medical Genetics Centre, Munich, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schön
authors.affiliation: Medical Genetics Centre, Munich, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Abicht
authors.affiliation: Medical Genetics Centre, Munich, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Rautenstrauss
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland.
authors.forename: Henna
authors.initials: H
authors.lastname: Tyynismaa
authors.affiliation: Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Maggie C
authors.initials: MC
authors.lastname: Walter
authors.affiliation: Institute for Clinical Chemistry, University Hospital Zurich, University of Zurich, Zurich, Switzerland.|Competence Center for Personalized Medicine (CC-PM), Zurich, Switzerland.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hornemann
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, 00290, Helsinki, Finland. emil.ylikallio@helsinki.fi.
authors.forename: Emil
authors.initials: E
authors.lastname: Ylikallio
mesh_terms: D017668:Age of Onset; D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001369:Axons / Q000473:pathology; D005260:Female; D005387:Finland; D005799:Genes, Dominant; D005858:Germany; D006239:Haplotypes; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000235:genetics*; D006801:Humans; D000067562:Late Onset Disorders / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D051102:Serine C-Palmitoyltransferase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000071075:Small Fiber Neuropathy / Q000235:genetics; D013107:Sphingolipids / Q000097:blood; D013379:Substrate Specificity
chemical_list: D013107:Sphingolipids; C495089:SPTLC2 protein, human; D051102:Serine C-Palmitoyltransferase
keywords: Hereditary sensory autonomic neuropathy; Neuropathy; Serine palmitoyl-CoA transferase; Sphingolipid