Novel cerebrospinal fluid biomarkers of glucose transporter type 1 deficiency syndrome: Implications beyond the brain's energy deficit

Tessa M. A. Peters; Jona Merx; Pieter C. Kooijman; Marek Noga; Siebolt de Boer; Loes A. van Gemert; Guido Salden; Udo F. H. Engelke; Dirk J. Lefeber; Rianne E. van Outersterp; Giel Berden; Thomas Jan Boltje; Rafael Artuch; Leticia Pías; Ángeles García‐Cazorla; Ivo Barić; Beat Thöny; Jos Oomens; Jonathan Martens; Ron A. Wevers; Marcel M. Verbeek; Karlien L. M. Coene; Michèl A. A. P. Willemsen

doi:10.1002/jimd.12554

Novel cerebrospinal fluid biomarkers of glucose transporter type 1 deficiency syndrome: Implications beyond the brain's energy deficit

Tessa M. A. Peters, Jona Merx, Pieter C. Kooijman, Marek Noga, Siebolt de Boer, Loes A. van Gemert, Guido Salden, Udo F. H. Engelke, Dirk J. Lefeber, Rianne E. van Outersterp, Giel Berden, Thomas Jan Boltje, Rafael Artuch, Leticia Pías, Ángeles García‐Cazorla, Ivo Barić, Beat Thöny, Jos Oomens, Jonathan Martens, Ron A. WeversMarcel M. Verbeek, Karlien L. M. Coene, Michèl A. A. P. Willemsen

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Abstract

We used next-generation metabolic screening to identify new biomarkers for improved diagnosis and pathophysiological understanding of glucose transporter type 1 deficiency syndrome (GLUT1DS), comparing metabolic cerebrospinal fluid (CSF) profiles from 12 patients to those of 116 controls. This confirmed decreased CSF glucose and lactate levels in patients with GLUT1DS and increased glutamine at group level. We identified three novel biomarkers significantly decreased in patients, namely gluconic + galactonic acid, xylose-α1-3-glucose, and xylose-α1-3-xylose-α1-3-glucose, of which the latter two have not previously been identified in body fluids. CSF concentrations of gluconic + galactonic acid may be reduced as these metabolites could serve as alternative substrates for the pentose phosphate pathway. Xylose-α1-3-glucose and xylose-α1-3-xylose-α1-3-glucose may originate from glycosylated proteins; their decreased levels are hypothetically the consequence of insufficient glucose, one of two substrates for O-glucosylation. Since many proteins are O-glucosylated, this deficiency may affect cellular processes and thus contribute to GLUT1DS pathophysiology. The novel CSF biomarkers have the potential to improve the biochemical diagnosis of GLUT1DS. Our findings imply that brain glucose deficiency in GLUT1DS may cause disruptions at the cellular level that go beyond energy metabolism, underlining the importance of developing treatment strategies that directly target cerebral glucose uptake.

Original language	English
Pages (from-to)	66-75
Number of pages	10
Journal	Journal of Inherited Metabolic Disease
Volume	46
Issue number	1
Early online date	10 Sept 2022
DOIs	https://doi.org/10.1002/jimd.12554
Publication status	Published - Jan 2023
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.

Funding

The study was funded by Stofwisselkracht under the project name of “Innovative diagnostics in cerebrospinal fluid of patients with neurometabolic disorders” (KLM Coene and MM Verbeek). Michèl A. A. P. Willemsen received an unrestricted grant from the Glut1 Deficiency Foundation (Owingsville, USA). Furthermore, the authors gratefully acknowledge the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO) for the support of the FELIX Laboratory. This work was supported by the NWO division Exact and Natural Sciences (grant numbers TTW 15769, TKI‐LIFT 731.017.419) and Radboud University through an interfaculty collaboration grant. Lastly, Marek Noga was funded by Metakids for the project “Intracellular nucleotide(sugar) fluxomics as a novel strategy to unravel IEMs”, 2019‐02b‐UMD. The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors. Loes van Gemert reports grants from the Glut1 Deficiency Foundation, outside the submitted work. Ángeles García‐Cazorla has a patent P2021130532 pending. The remaining authors declare no conflicts of interest.

Funders	Funder number
NWO division Exact and Natural Sciences	TTW 15769, TKI‐LIFT 731.017.419
Glut1 Deficiency Foundation
Radboud Universitair Medisch Centrum

Keywords

O-glucosylation
SLC2A1
next-generation metabolic screening
oligosaccharides
untargeted metabolomics

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Cite this

Peters, T. M. A., Merx, J., Kooijman, P. C., Noga, M., Boer, S. D., Gemert, L. A. V., Salden, G., Engelke, U. F. H., Lefeber, D. J., Outersterp, R. E. V., Berden, G., Boltje, T. J., Artuch, R., Pías, L., García‐Cazorla, Á., Barić, I., Thöny, B., Oomens, J., Martens, J., ... Willemsen, M. A. A. P. (2023). Novel cerebrospinal fluid biomarkers of glucose transporter type 1 deficiency syndrome: Implications beyond the brain's energy deficit. Journal of Inherited Metabolic Disease, 46(1), 66-75. https://doi.org/10.1002/jimd.12554

@article{69162eefe09143aba93c88752f342192,

title = "Novel cerebrospinal fluid biomarkers of glucose transporter type 1 deficiency syndrome: Implications beyond the brain's energy deficit",

abstract = "We used next-generation metabolic screening to identify new biomarkers for improved diagnosis and pathophysiological understanding of glucose transporter type 1 deficiency syndrome (GLUT1DS), comparing metabolic cerebrospinal fluid (CSF) profiles from 12 patients to those of 116 controls. This confirmed decreased CSF glucose and lactate levels in patients with GLUT1DS and increased glutamine at group level. We identified three novel biomarkers significantly decreased in patients, namely gluconic + galactonic acid, xylose-α1-3-glucose, and xylose-α1-3-xylose-α1-3-glucose, of which the latter two have not previously been identified in body fluids. CSF concentrations of gluconic + galactonic acid may be reduced as these metabolites could serve as alternative substrates for the pentose phosphate pathway. Xylose-α1-3-glucose and xylose-α1-3-xylose-α1-3-glucose may originate from glycosylated proteins; their decreased levels are hypothetically the consequence of insufficient glucose, one of two substrates for O-glucosylation. Since many proteins are O-glucosylated, this deficiency may affect cellular processes and thus contribute to GLUT1DS pathophysiology. The novel CSF biomarkers have the potential to improve the biochemical diagnosis of GLUT1DS. Our findings imply that brain glucose deficiency in GLUT1DS may cause disruptions at the cellular level that go beyond energy metabolism, underlining the importance of developing treatment strategies that directly target cerebral glucose uptake.",

keywords = "O-glucosylation, SLC2A1, next-generation metabolic screening, oligosaccharides, untargeted metabolomics",

author = "Peters, {Tessa M. A.} and Jona Merx and Kooijman, {Pieter C.} and Marek Noga and Boer, {Siebolt de} and Gemert, {Loes A. van} and Guido Salden and Engelke, {Udo F. H.} and Lefeber, {Dirk J.} and Outersterp, {Rianne E. van} and Giel Berden and Boltje, {Thomas Jan} and Rafael Artuch and Leticia P{\'i}as and {\'A}ngeles Garc{\'i}a‐Cazorla and Ivo Bari{\'c} and Beat Th{\"o}ny and Jos Oomens and Jonathan Martens and Wevers, {Ron A.} and Verbeek, {Marcel M.} and Coene, {Karlien L. M.} and Willemsen, {Mich{\`e}l A. A. P.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.",

year = "2023",

month = jan,

doi = "10.1002/jimd.12554",

language = "English",

volume = "46",

pages = "66--75",

journal = "Journal of Inherited Metabolic Disease",

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Peters, TMA, Merx, J, Kooijman, PC, Noga, M, Boer, SD, Gemert, LAV, Salden, G, Engelke, UFH, Lefeber, DJ, Outersterp, REV, Berden, G, Boltje, TJ, Artuch, R, Pías, L, García‐Cazorla, Á, Barić, I, Thöny, B, Oomens, J, Martens, J, Wevers, RA, Verbeek, MM, Coene, KLM & Willemsen, MAAP 2023, 'Novel cerebrospinal fluid biomarkers of glucose transporter type 1 deficiency syndrome: Implications beyond the brain's energy deficit', Journal of Inherited Metabolic Disease, vol. 46, no. 1, pp. 66-75. https://doi.org/10.1002/jimd.12554

TY - JOUR

T1 - Novel cerebrospinal fluid biomarkers of glucose transporter type 1 deficiency syndrome: Implications beyond the brain's energy deficit

AU - Peters, Tessa M. A.

AU - Merx, Jona

AU - Kooijman, Pieter C.

AU - Noga, Marek

AU - Boer, Siebolt de

AU - Gemert, Loes A. van

AU - Salden, Guido

AU - Engelke, Udo F. H.

AU - Lefeber, Dirk J.

AU - Outersterp, Rianne E. van

AU - Berden, Giel

AU - Boltje, Thomas Jan

AU - Artuch, Rafael

AU - Pías, Leticia

AU - García‐Cazorla, Ángeles

AU - Barić, Ivo

AU - Thöny, Beat

AU - Oomens, Jos

AU - Martens, Jonathan

AU - Wevers, Ron A.

AU - Verbeek, Marcel M.

AU - Coene, Karlien L. M.

AU - Willemsen, Michèl A. A. P.

PY - 2023/1

Y1 - 2023/1

N2 - We used next-generation metabolic screening to identify new biomarkers for improved diagnosis and pathophysiological understanding of glucose transporter type 1 deficiency syndrome (GLUT1DS), comparing metabolic cerebrospinal fluid (CSF) profiles from 12 patients to those of 116 controls. This confirmed decreased CSF glucose and lactate levels in patients with GLUT1DS and increased glutamine at group level. We identified three novel biomarkers significantly decreased in patients, namely gluconic + galactonic acid, xylose-α1-3-glucose, and xylose-α1-3-xylose-α1-3-glucose, of which the latter two have not previously been identified in body fluids. CSF concentrations of gluconic + galactonic acid may be reduced as these metabolites could serve as alternative substrates for the pentose phosphate pathway. Xylose-α1-3-glucose and xylose-α1-3-xylose-α1-3-glucose may originate from glycosylated proteins; their decreased levels are hypothetically the consequence of insufficient glucose, one of two substrates for O-glucosylation. Since many proteins are O-glucosylated, this deficiency may affect cellular processes and thus contribute to GLUT1DS pathophysiology. The novel CSF biomarkers have the potential to improve the biochemical diagnosis of GLUT1DS. Our findings imply that brain glucose deficiency in GLUT1DS may cause disruptions at the cellular level that go beyond energy metabolism, underlining the importance of developing treatment strategies that directly target cerebral glucose uptake.

AB - We used next-generation metabolic screening to identify new biomarkers for improved diagnosis and pathophysiological understanding of glucose transporter type 1 deficiency syndrome (GLUT1DS), comparing metabolic cerebrospinal fluid (CSF) profiles from 12 patients to those of 116 controls. This confirmed decreased CSF glucose and lactate levels in patients with GLUT1DS and increased glutamine at group level. We identified three novel biomarkers significantly decreased in patients, namely gluconic + galactonic acid, xylose-α1-3-glucose, and xylose-α1-3-xylose-α1-3-glucose, of which the latter two have not previously been identified in body fluids. CSF concentrations of gluconic + galactonic acid may be reduced as these metabolites could serve as alternative substrates for the pentose phosphate pathway. Xylose-α1-3-glucose and xylose-α1-3-xylose-α1-3-glucose may originate from glycosylated proteins; their decreased levels are hypothetically the consequence of insufficient glucose, one of two substrates for O-glucosylation. Since many proteins are O-glucosylated, this deficiency may affect cellular processes and thus contribute to GLUT1DS pathophysiology. The novel CSF biomarkers have the potential to improve the biochemical diagnosis of GLUT1DS. Our findings imply that brain glucose deficiency in GLUT1DS may cause disruptions at the cellular level that go beyond energy metabolism, underlining the importance of developing treatment strategies that directly target cerebral glucose uptake.

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KW - SLC2A1

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KW - oligosaccharides

KW - untargeted metabolomics

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DO - 10.1002/jimd.12554

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Novel cerebrospinal fluid biomarkers of glucose transporter type 1 deficiency syndrome: Implications beyond the brain's energy deficit

Abstract

Bibliographical note

Funding

Keywords

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