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Clinical and metabolic consequences of L-serine supplementation in hereditary sensory and autonomic neuropathy type 1C

Hereditary sensory neuropathy type 1 (HSAN1) may be the first genetic neuropathy amenable to a specific mechanism-based treatment, as L-serine supplementation can be used to lower the neurotoxic levels of 1-deoxysphingolipids (1-deoxySL) that cause the neurodegeneration. The treatment is so far unte...

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Autores principales: Auranen, Mari, Toppila, Jussi, Suriyanarayanan, Saranya, Lone, Museer A., Paetau, Anders, Tyynismaa, Henna, Hornemann, Thorsten, Ylikallio, Emil
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701299/
https://www.ncbi.nlm.nih.gov/pubmed/29042446
http://dx.doi.org/10.1101/mcs.a002212
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author Auranen, Mari
Toppila, Jussi
Suriyanarayanan, Saranya
Lone, Museer A.
Paetau, Anders
Tyynismaa, Henna
Hornemann, Thorsten
Ylikallio, Emil
author_facet Auranen, Mari
Toppila, Jussi
Suriyanarayanan, Saranya
Lone, Museer A.
Paetau, Anders
Tyynismaa, Henna
Hornemann, Thorsten
Ylikallio, Emil
author_sort Auranen, Mari
collection PubMed
description Hereditary sensory neuropathy type 1 (HSAN1) may be the first genetic neuropathy amenable to a specific mechanism-based treatment, as L-serine supplementation can be used to lower the neurotoxic levels of 1-deoxysphingolipids (1-deoxySL) that cause the neurodegeneration. The treatment is so far untested in HSAN1C caused by variants in the serine palmitoyl transferase subunit 2 (SPTLC2) gene. The aim of this study was to establish whether oral L-serine lowers 1-deoxySL in a patient with HSAN1C, to perform a dose escalation to find the minimal effective dose, and to assess the safety profile and global metabolic effects of the treatment. Our patient underwent a 52-wk treatment in which the L-serine dose was titrated up to 400 mg/kg/day. She was followed up by repeated clinical examination, nerve conduction testing, and skin biopsies to document effects on small nerve fibers. Serum was assayed for 1-deoxySL and metabolomics analysis of 111 metabolites. We found a robust lowering of 1-deoxySL, which correlated in a near-linear fashion with increased serum L-serine levels. Metabolomics analysis showed a modest elevation in glycine and a marked reduction in the level of cytosine, whereas most of the other assayed metabolites did not change. There were no direct side effects from the treatment, but the patient developed a transitory toe ulceration during the course of the study. The Charcot–Marie–Tooth neuropathy score increased by 1 point. We conclude that oral supplementation of L-serine decreases 1-deoxySL in HSAN1C without major global effects on metabolism. L-serine is therefore a potential treatment for HSAN1C.
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spelling pubmed-57012992017-12-04 Clinical and metabolic consequences of L-serine supplementation in hereditary sensory and autonomic neuropathy type 1C Auranen, Mari Toppila, Jussi Suriyanarayanan, Saranya Lone, Museer A. Paetau, Anders Tyynismaa, Henna Hornemann, Thorsten Ylikallio, Emil Cold Spring Harb Mol Case Stud Research Report Hereditary sensory neuropathy type 1 (HSAN1) may be the first genetic neuropathy amenable to a specific mechanism-based treatment, as L-serine supplementation can be used to lower the neurotoxic levels of 1-deoxysphingolipids (1-deoxySL) that cause the neurodegeneration. The treatment is so far untested in HSAN1C caused by variants in the serine palmitoyl transferase subunit 2 (SPTLC2) gene. The aim of this study was to establish whether oral L-serine lowers 1-deoxySL in a patient with HSAN1C, to perform a dose escalation to find the minimal effective dose, and to assess the safety profile and global metabolic effects of the treatment. Our patient underwent a 52-wk treatment in which the L-serine dose was titrated up to 400 mg/kg/day. She was followed up by repeated clinical examination, nerve conduction testing, and skin biopsies to document effects on small nerve fibers. Serum was assayed for 1-deoxySL and metabolomics analysis of 111 metabolites. We found a robust lowering of 1-deoxySL, which correlated in a near-linear fashion with increased serum L-serine levels. Metabolomics analysis showed a modest elevation in glycine and a marked reduction in the level of cytosine, whereas most of the other assayed metabolites did not change. There were no direct side effects from the treatment, but the patient developed a transitory toe ulceration during the course of the study. The Charcot–Marie–Tooth neuropathy score increased by 1 point. We conclude that oral supplementation of L-serine decreases 1-deoxySL in HSAN1C without major global effects on metabolism. L-serine is therefore a potential treatment for HSAN1C. Cold Spring Harbor Laboratory Press 2017-11 /pmc/articles/PMC5701299/ /pubmed/29042446 http://dx.doi.org/10.1101/mcs.a002212 Text en © 2017 Auranen et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/) , which permits reuse and redistribution, except for commercial purposes, provided that the original author and source are credited.
spellingShingle Research Report
Auranen, Mari
Toppila, Jussi
Suriyanarayanan, Saranya
Lone, Museer A.
Paetau, Anders
Tyynismaa, Henna
Hornemann, Thorsten
Ylikallio, Emil
Clinical and metabolic consequences of L-serine supplementation in hereditary sensory and autonomic neuropathy type 1C
title Clinical and metabolic consequences of L-serine supplementation in hereditary sensory and autonomic neuropathy type 1C
title_full Clinical and metabolic consequences of L-serine supplementation in hereditary sensory and autonomic neuropathy type 1C
title_fullStr Clinical and metabolic consequences of L-serine supplementation in hereditary sensory and autonomic neuropathy type 1C
title_full_unstemmed Clinical and metabolic consequences of L-serine supplementation in hereditary sensory and autonomic neuropathy type 1C
title_short Clinical and metabolic consequences of L-serine supplementation in hereditary sensory and autonomic neuropathy type 1C
title_sort clinical and metabolic consequences of l-serine supplementation in hereditary sensory and autonomic neuropathy type 1c
topic Research Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701299/
https://www.ncbi.nlm.nih.gov/pubmed/29042446
http://dx.doi.org/10.1101/mcs.a002212
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