Discovery of novel diagnostic biomarkers for Sjögren-Larsson syndrome by untargeted lipidomics

Frédéric M Vaz; Pippa Staps; Jan Bert van Klinken; Henk van Lenthe; Martin Vervaart; Ronald J A Wanders; Mia L Pras-Raves; Michel van Weeghel; Gajja S Salomons; Sacha Ferdinandusse; Ron A Wevers; Michèl A A P Willemsen

doi:https://doi.org/10.1016/j.bbalip.2023.159447

Discovery of novel diagnostic biomarkers for Sjögren-Larsson syndrome by untargeted lipidomics

Frédéric M Vaz, Pippa Staps, Jan Bert van Klinken, Henk van Lenthe, Martin Vervaart, Ronald J A Wanders, Mia L Pras-Raves, Michel van Weeghel, Gajja S Salomons, Sacha Ferdinandusse, Ron A Wevers, Michèl A A P Willemsen

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

AIM: Sjögren-Larsson syndrome (SLS) is a rare neurometabolic disorder that mainly affects brain, eye and skin and is caused by deficiency of fatty aldehyde dehydrogenase. Our recent finding of a profoundly disturbed brain tissue lipidome in SLS prompted us to search for similar biomarkers in plasma as no functional test in blood is available for SLS.

METHODS AND RESULTS: We performed plasma lipidomics and used a newly developed bioinformatics tool to mine the untargeted part of the SLS plasma and brain lipidome to search for SLS biomarkers. Plasma lipidomics showed disturbed ether lipid metabolism in known lipid classes. Untargeted lipidomics of both plasma and brain (white and grey matter) uncovered two new endogenous lipid classes highly elevated in SLS. The first biomarker group were alkylphosphocholines/ethanolamines containing different lengths of alkyl-chains where some alkylphosphocholines were > 600-fold elevated in SLS plasma. The second group of biomarkers were a set of 5 features of unknown structure. Fragmentation studies suggested that they contain ubiquinol and phosphocholine and one feature was also found as a glucuronide conjugate in plasma. The plasma features were highly distinctive for SLS with levels >100-1000-fold the level in controls, if present at all. We speculate on the origin of the alkylphosphocholines/ethanolamines and the nature of the ubiquinol-containing metabolites.

CONCLUSIONS: The metabolites identified in this study represent novel endogenous lipid classes thus far unknown in humans. They represent the first plasma metabolite SLS-biomarkers and may also yield more insight into SLS pathophysiology.

Original language	English
Article number	159447
Pages (from-to)	159447
Journal	BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
Volume	1869
Issue number	2
Early online date	3 Jan 2024
DOIs	https://doi.org/10.1016/j.bbalip.2023.159447
Publication status	Published - 1 Mar 2024

Keywords

ALDH3A2
Alkylphosphocholines
Alkylphosphoethanolamines
Farnesol metabolism
Pathophysiology
Plasma biomarkers
Ubiqinol-like molecules
Ubiquinol
Untargeted lipidomics pipeline

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https://doi.org/10.1016/j.bbalip.2023.159447

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Vaz, F. M., Staps, P., van Klinken, J. B., van Lenthe, H., Vervaart, M., Wanders, R. J. A., Pras-Raves, M. L., van Weeghel, M., Salomons, G. S., Ferdinandusse, S., Wevers, R. A., & Willemsen, M. A. A. P. (2024). Discovery of novel diagnostic biomarkers for Sjögren-Larsson syndrome by untargeted lipidomics. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, 1869(2), 159447. Article 159447. https://doi.org/10.1016/j.bbalip.2023.159447

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title = "Discovery of novel diagnostic biomarkers for Sj{\"o}gren-Larsson syndrome by untargeted lipidomics",

abstract = "AIM: Sj{\"o}gren-Larsson syndrome (SLS) is a rare neurometabolic disorder that mainly affects brain, eye and skin and is caused by deficiency of fatty aldehyde dehydrogenase. Our recent finding of a profoundly disturbed brain tissue lipidome in SLS prompted us to search for similar biomarkers in plasma as no functional test in blood is available for SLS.METHODS AND RESULTS: We performed plasma lipidomics and used a newly developed bioinformatics tool to mine the untargeted part of the SLS plasma and brain lipidome to search for SLS biomarkers. Plasma lipidomics showed disturbed ether lipid metabolism in known lipid classes. Untargeted lipidomics of both plasma and brain (white and grey matter) uncovered two new endogenous lipid classes highly elevated in SLS. The first biomarker group were alkylphosphocholines/ethanolamines containing different lengths of alkyl-chains where some alkylphosphocholines were > 600-fold elevated in SLS plasma. The second group of biomarkers were a set of 5 features of unknown structure. Fragmentation studies suggested that they contain ubiquinol and phosphocholine and one feature was also found as a glucuronide conjugate in plasma. The plasma features were highly distinctive for SLS with levels >100-1000-fold the level in controls, if present at all. We speculate on the origin of the alkylphosphocholines/ethanolamines and the nature of the ubiquinol-containing metabolites.CONCLUSIONS: The metabolites identified in this study represent novel endogenous lipid classes thus far unknown in humans. They represent the first plasma metabolite SLS-biomarkers and may also yield more insight into SLS pathophysiology.",

keywords = "ALDH3A2, Alkylphosphocholines, Alkylphosphoethanolamines, Farnesol metabolism, Pathophysiology, Plasma biomarkers, Ubiqinol-like molecules, Ubiquinol, Untargeted lipidomics pipeline",

author = "Vaz, {Fr{\'e}d{\'e}ric M} and Pippa Staps and {van Klinken}, {Jan Bert} and {van Lenthe}, Henk and Martin Vervaart and Wanders, {Ronald J A} and Pras-Raves, {Mia L} and {van Weeghel}, Michel and Salomons, {Gajja S} and Sacha Ferdinandusse and Wevers, {Ron A} and Willemsen, {Mich{\`e}l A A P}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = mar,

day = "1",

doi = "https://doi.org/10.1016/j.bbalip.2023.159447",

language = "English",

volume = "1869",

pages = "159447",

journal = "BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS",

issn = "1388-1981",

publisher = "Elsevier",

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Vaz, FM, Staps, P, van Klinken, JB , van Lenthe, H , Vervaart, M, Wanders, RJA, Pras-Raves, ML , van Weeghel, M , Salomons, GS , Ferdinandusse, S, Wevers, RA & Willemsen, MAAP 2024, 'Discovery of novel diagnostic biomarkers for Sjögren-Larsson syndrome by untargeted lipidomics', BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, vol. 1869, no. 2, 159447, pp. 159447. https://doi.org/10.1016/j.bbalip.2023.159447

TY - JOUR

T1 - Discovery of novel diagnostic biomarkers for Sjögren-Larsson syndrome by untargeted lipidomics

AU - Vaz, Frédéric M

AU - Staps, Pippa

AU - van Klinken, Jan Bert

AU - van Lenthe, Henk

AU - Vervaart, Martin

AU - Wanders, Ronald J A

AU - Pras-Raves, Mia L

AU - van Weeghel, Michel

AU - Salomons, Gajja S

AU - Ferdinandusse, Sacha

AU - Wevers, Ron A

AU - Willemsen, Michèl A A P

PY - 2024/3/1

Y1 - 2024/3/1

N2 - AIM: Sjögren-Larsson syndrome (SLS) is a rare neurometabolic disorder that mainly affects brain, eye and skin and is caused by deficiency of fatty aldehyde dehydrogenase. Our recent finding of a profoundly disturbed brain tissue lipidome in SLS prompted us to search for similar biomarkers in plasma as no functional test in blood is available for SLS.METHODS AND RESULTS: We performed plasma lipidomics and used a newly developed bioinformatics tool to mine the untargeted part of the SLS plasma and brain lipidome to search for SLS biomarkers. Plasma lipidomics showed disturbed ether lipid metabolism in known lipid classes. Untargeted lipidomics of both plasma and brain (white and grey matter) uncovered two new endogenous lipid classes highly elevated in SLS. The first biomarker group were alkylphosphocholines/ethanolamines containing different lengths of alkyl-chains where some alkylphosphocholines were > 600-fold elevated in SLS plasma. The second group of biomarkers were a set of 5 features of unknown structure. Fragmentation studies suggested that they contain ubiquinol and phosphocholine and one feature was also found as a glucuronide conjugate in plasma. The plasma features were highly distinctive for SLS with levels >100-1000-fold the level in controls, if present at all. We speculate on the origin of the alkylphosphocholines/ethanolamines and the nature of the ubiquinol-containing metabolites.CONCLUSIONS: The metabolites identified in this study represent novel endogenous lipid classes thus far unknown in humans. They represent the first plasma metabolite SLS-biomarkers and may also yield more insight into SLS pathophysiology.

AB - AIM: Sjögren-Larsson syndrome (SLS) is a rare neurometabolic disorder that mainly affects brain, eye and skin and is caused by deficiency of fatty aldehyde dehydrogenase. Our recent finding of a profoundly disturbed brain tissue lipidome in SLS prompted us to search for similar biomarkers in plasma as no functional test in blood is available for SLS.METHODS AND RESULTS: We performed plasma lipidomics and used a newly developed bioinformatics tool to mine the untargeted part of the SLS plasma and brain lipidome to search for SLS biomarkers. Plasma lipidomics showed disturbed ether lipid metabolism in known lipid classes. Untargeted lipidomics of both plasma and brain (white and grey matter) uncovered two new endogenous lipid classes highly elevated in SLS. The first biomarker group were alkylphosphocholines/ethanolamines containing different lengths of alkyl-chains where some alkylphosphocholines were > 600-fold elevated in SLS plasma. The second group of biomarkers were a set of 5 features of unknown structure. Fragmentation studies suggested that they contain ubiquinol and phosphocholine and one feature was also found as a glucuronide conjugate in plasma. The plasma features were highly distinctive for SLS with levels >100-1000-fold the level in controls, if present at all. We speculate on the origin of the alkylphosphocholines/ethanolamines and the nature of the ubiquinol-containing metabolites.CONCLUSIONS: The metabolites identified in this study represent novel endogenous lipid classes thus far unknown in humans. They represent the first plasma metabolite SLS-biomarkers and may also yield more insight into SLS pathophysiology.

KW - ALDH3A2

KW - Alkylphosphocholines

KW - Alkylphosphoethanolamines

KW - Farnesol metabolism

KW - Pathophysiology

KW - Plasma biomarkers

KW - Ubiqinol-like molecules

KW - Ubiquinol

KW - Untargeted lipidomics pipeline

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U2 - https://doi.org/10.1016/j.bbalip.2023.159447

DO - https://doi.org/10.1016/j.bbalip.2023.159447

M3 - Article

C2 - 38181883

SN - 1388-1981

VL - 1869

SP - 159447

JO - BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS

JF - BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS

IS - 2

M1 - 159447

ER -

Discovery of novel diagnostic biomarkers for Sjögren-Larsson syndrome by untargeted lipidomics

Abstract

Keywords

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