Metabolomic Discovery of Novel Urinary Galabiosylceramide Analogs as Fabry Disease Biomarkers

Boutin, Michel; Auray‐Blais, Christiane

doi:10.1007/s13361-014-1060-3

Cited by 44 publications

(47 citation statements)

References 26 publications

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“…The hypothesis that increased levels of plasma and (possibly) urinary lyso-Gb 3 analog at m/z 836 are an earlier biomarker of progressive heart disease, and that urinary excretion of Gb 3 is a specific biomarker of FD nephropathy, warrants further research studies [74] with larger, carefully selected cardiac and renal patient cohorts.…”

Section: Discussionmentioning

confidence: 99%

Variations in the GLA gene correlate with globotriaosylceramide and globotriaosylsphingosine analog levels in urine and plasma

Ferreira

Auray‐Blais

Boutin

et al. 2015

Clinica Chimica Acta

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Recent data have shown that lyso-Gb3, the deacylated derivative of globotriaosylceramide (Gb3), is possibly involved in the pathogenesis of Fabry disease (FD) and might be a clinically useful biomarker of its metabolic load. To test this hypothesis, we assayed Gb3 and lyso-Gb3 and related analogs in plasma and/or urine samples of 12 clinically well-characterized subjects carrying several different GLA variant alleles associated with a wide range of residual α-galactosidase A activities. Urinary Gb3 was measured by HPLC–MS/MS; plasma and urinary lyso-Gb3 and related analogs were measured by UPLC–MS/MS. Individual profiles of Gb3 and lyso-Gb3 and related analogs closely correlated with the phenotypic data for each subject, discerning the classical FD patient from the two patients carrying cardiac variants as well as these from all the others without FD. The lyso-Gb3 analog at m/z 836 was found at increased levels only in patients manifesting clinically severe heart disease, irrespective of the pathogenicity of the GLA variant they carried. This finding suggests that this lyso-Gb3 analog might be an earlier biomarker of progressive heart disease, non-specific of the FD cardiomyopathy. The possibility that urinary Gb3 is a specific marker of kidney involvement in FD deserves further study.

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Section: Discussionmentioning

confidence: 99%

Variations in the GLA gene correlate with globotriaosylceramide and globotriaosylsphingosine analog levels in urine and plasma

Ferreira

Auray‐Blais

Boutin

et al. 2015

Clinica Chimica Acta

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“…These amphiphilic molecules composed of a glycan head group and ceramide backbone are involved in protein interaction, receptor regulation, initiation and modulation of signal transduction, as well as cell recognition and differentiation [2]. Given these, perturbations in glycosphingolipid metabolism have been recognized as hallmark in a myriad of pathologies including neurological [4, 5], autoimmune [6], and lysosomal storage diseases [7] among others. Recent literature also indicates their potential use as therapeutic agents in cancer and autoimmune diseases due to their immunogenic characteristics [8].…”

Section: Introductionmentioning

confidence: 99%

Structural Analysis of Unsaturated Glycosphingolipids Using Shotgun Ozone-Induced Dissociation Mass Spectrometry

Barrientos

Zhang³

2017

J. Am. Soc. Mass Spectrom.

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Glycosphingolipids are essential biomolecules widely distributed across biological kingdoms yet remain relatively underexplored owing to both compositional and structural complexity. While the glycan head group has been the subject of most studies, there is paucity of reports on the lipid moiety, particularly the location of unsaturation. In this paper, ozone-induced dissociation mass spectrometry (OzID-MS) implemented in a traveling wave-based quadrupole time-of-flight (Q-ToF) mass spectrometer was applied to study unsaturated glycosphingolipids using shotgun approach. Resulting high resolution mass spectra facilitated the unambiguous identification of diagnostic OzID product ions. Using [M+Na]+ adducts of authentic standards, we observed that the long chain base and fatty acyl unsaturation had distinct reactivity with ozone. The reactivity of unsaturation in the fatty acyl chain was about eight-fold higher than that in the long chain base, which enables their straightforward differentiation. Influence of the head group, fatty acyl hydroxylation and length of fatty acyl chain on the oxidative cleavage of double bonds was also observed. Application of this technique to bovine brain galactocerebrosides revealed co-isolated isobaric and regioisomeric species which otherwise would be incompletely identified using contemporary collision-induced dissociation (CID) alone. These results highlight the potential of OzID-MS in glycosphingolipids research, which not only provides complementary structural information to existing CID technique but also facilitates de novo structural determination of these complex biomolecules.

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“…Our ability to convert sulfatides to a derivative that can be analyzed in positive-ion MS/MS is expected to be valuable for multiplexing NBS of MLD with other diseases, including a panel of lysosomal storage diseases for which we have developed highly robust NBS assays in positive-ion mode (15). UHPLC-MS/MS in positive-ion mode can be used to simultaneously monitor the activity of several enzymes and a panel of biomarkers; for example, psychosine for Krabbe disease (16, 17), lyso-Gb 3 for Fabry disease (18), glucosylsphingosine for Gaucher disease (19), and sulfatides for MLD. This will be possible with inject-to-inject times that are short enough for NBS.…”

Section: Discussionmentioning

confidence: 99%

Sulfatide Analysis by Mass Spectrometry for Screening of Metachromatic Leukodystrophy in Dried Blood and Urine Samples

Spáčil¹,

Kumar²,

Liao³

et al. 2016

Clinical Chemistry

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BACKGROUND Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder caused by deficiency in arylsulfatase A activity, leading to accumulation of sulfatide substrates. Diagnostic and monitoring procedures include demonstration of reduced arylsulfatase A activity in peripheral blood leukocytes or detection of sulfatides in urine. However, the development of a screening test is challenging because of instability of the enzyme in dried blood spots (DBS), the widespread occurrence of pseudodeficiency alleles, and the lack of available urine samples from newborn screening programs. METHODS We measured individual sulfatide profiles in DBS and dried urine spots (DUS) from MLD patients with LC-MS/MS to identify markers with the discriminatory power to differentiate affected individuals from controls. We also developed a method for converting all sulfatide molecular species into a single species, allowing quantification in positive-ion mode upon derivatization. RESULTS In DBS from MLD patients, we found up to 23.2-fold and 5.1-fold differences in total sulfatide concentrations for early- and late-onset MLD, respectively, compared with controls and pseudodeficiencies. Corresponding DUS revealed up to 164-fold and 78-fold differences for early- and late-onset MLD patient samples compared with controls. The use of sulfatides converted to a single species simplified the analysis and increased detection sensitivity in positive-ion mode, providing a second option for sulfatide analysis. CONCLUSIONS This study of sulfatides in DBS and DUS suggests the feasibility of the mass spectrometry method for newborn screening of MLD and sets the stage for a larger-scale newborn screening pilot study.

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Metabolomic Discovery of Novel Urinary Galabiosylceramide Analogs as Fabry Disease Biomarkers

Cited by 44 publications

References 26 publications

Variations in the GLA gene correlate with globotriaosylceramide and globotriaosylsphingosine analog levels in urine and plasma

Variations in the GLA gene correlate with globotriaosylceramide and globotriaosylsphingosine analog levels in urine and plasma

Structural Analysis of Unsaturated Glycosphingolipids Using Shotgun Ozone-Induced Dissociation Mass Spectrometry

Sulfatide Analysis by Mass Spectrometry for Screening of Metachromatic Leukodystrophy in Dried Blood and Urine Samples

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