title: Oral L-serine supplementation reduces  production of neurotoxic deoxysphingolipids  in mice and humans with hereditary sensory  autonomic neuropathy type 1.
abstract: Hereditary sensory and autonomic neuropathy type 1 (HSAN1) causes sensory loss that predominantly affects the lower limbs, often preceded by hyperpathia and spontaneous shooting or lancinating pain. It is caused by several missense mutations in the genes encoding 2 of the 3 subunits of the enzyme serine palmitoyltransferase (SPT). The mutant forms of the enzyme show a shift from their canonical substrate L-serine to the alternative substrate L-alanine. This shift leads to increased formation of neurotoxic deoxysphingolipids (dSLs). Our initial analysis showed that in HEK cells transfected with SPTLC1 mutants, dSL generation was modulated in vitro in the presence of various amino acids. We therefore examined whether in vivo specific amino acid substrate supplementation influenced dSL levels and disease severity in HSAN1. In mice bearing a transgene expressing the C133W SPTLC1 mutant linked to HSAN1, a 10% L-serine–enriched diet reduced dSL levels. L-serine supplementation also improved measures of motor and sensory performance as well as measures of male fertility. In contrast, a 10% L-alanine–enriched diet increased dSL levels and led to severe peripheral neuropathy. In a pilot study with 14 HSAN1 patients, L-serine supplementation similarly reduced dSL levels. These observations support the hypothesis that an altered substrate selectivity of the mutant SPT is key to the pathophysiology of HSAN1 and raise the prospect of l-serine supplementation as a first treatment option for this disorder.
authors: MGH Neuroscience Center, Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA.
authors: Kevin
authors: K
authors: Garofalo
authors: Anke
authors: A
authors: Penno
authors: Brian P
authors: BP
authors: Schmidt
authors: Ho-Joon
authors: HJ
authors: Lee
authors: Matthew P
authors: MP
authors: Frosch
authors: Arnold
authors: A
authors: von Eckardstein
authors: Robert H
authors: RH
authors: Brown
authors: Thorsten
authors: T
authors: Hornemann
authors: Florian S
authors: FS
authors: Eichler
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000409:Alanine / Q000633:toxicity; D000818:Animals; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D005260:Female; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007248:Infertility, Male / Q000188:drug therapy / Q000235:genetics; D008055:Lipids; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D020125:Mutation, Missense; D009498:Neurotoxins / Q000096:biosynthesis*; D058748:Pain Perception / Q000187:drug effects; D010865:Pilot Projects; D017354:Point Mutation; D011597:Psychomotor Performance / Q000187:drug effects; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology; D012694:Serine / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D051102:Serine C-Palmitoyltransferase / Q000172:deficiency / Q000235:genetics; D013107:Sphingolipids / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D013237:Stereoisomerism; D055815:Young Adult
chemical_list: D008055:Lipids; D009498:Neurotoxins; D013107:Sphingolipids; D012694:Serine; C487784:SPTLC1 protein, human; D051102:Serine C-Palmitoyltransferase; D013110:Sphingosine; D000409:Alanine; C408363:spisulosine