How well does urinary lyso-Gb3 function as a biomarker in Fabry disease?

Auray‐Blais, Christiane; Ntwari, Aimé; Clarke, Joe T.R.; Warnock, David G.; Oliveira, João Paulo; Young, Sarah P.; Millington, David S.; Bichet, Daniel G.; Sirrs, Sandra; West, Michael; Casey, Robin; Hwu, Wuh‐Liang; Keutzer, Joan; Zhang, X. Kate; Gagnon, René

doi:10.1016/j.cca.2010.07.038

Cited by 92 publications

(115 citation statements)

References 29 publications

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“…similar to the price of GLA activity assays). In terms of diagnostic accuracy, CE-MS also favourably compares to urinary Gb 3 , for which an AUC of 0.876 has been reported [33] (vs. 0.970 for CE-MS in our study), although lyso-Gb 3 seems to perform better than total Gb 3 [34]. In addition, because similarly accurate CE-MS based diagnostic models have been developed for a variety of other renal and cardiovascular diseases [13], [35], [36], [37], [38], [39], CE-MS may give hints to an alternative diagnosis in Fabry negative patients, i.e.…”

Section: Discussionsupporting

confidence: 45%

A Distinct Urinary Biomarker Pattern Characteristic of Female Fabry Patients That Mirrors Response to Enzyme Replacement Therapy

et al. 2011

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Female patients affected by Fabry disease, an X-linked lysosomal storage disorder, exhibit a wide spectrum of symptoms, which renders diagnosis, and treatment decisions challenging. No diagnostic test, other than sequencing of the alpha-galactosidase A gene, is available and no biomarker has been proven useful to screen for the disease, predict disease course and monitor response to enzyme replacement therapy. Here, we used urine proteomic analysis based on capillary electrophoresis coupled to mass spectrometry and identified a biomarker profile in adult female Fabry patients. Urine samples were taken from 35 treatment-naïve female Fabry patients and were compared to 89 age-matched healthy controls. We found a diagnostic biomarker pattern that exhibited 88.2% sensitivity and 97.8% specificity when tested in an independent validation cohort consisting of 17 treatment-naïve Fabry patients and 45 controls. The model remained highly specific when applied to additional control patients with a variety of other renal, metabolic and cardiovascular diseases. Several of the 64 identified diagnostic biomarkers showed correlations with measures of disease severity. Notably, most biomarkers responded to enzyme replacement therapy, and 8 of 11 treated patients scored negative for Fabry disease in the diagnostic model. In conclusion, we defined a urinary biomarker model that seems to be of diagnostic use for Fabry disease in female patients and may be used to monitor response to enzyme replacement therapy.

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Section: Discussionsupporting

confidence: 45%

A Distinct Urinary Biomarker Pattern Characteristic of Female Fabry Patients That Mirrors Response to Enzyme Replacement Therapy

et al. 2011

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“…Here we present a new method for the quantification of lysoGb3 based on ultraperformance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) and the use of [5,6,7,8,9] 13 C 5 -labeled lysoGb3 as the internal standard, which was synthesized for this particular purpose. In addition, we quantify a compound closely related to lysoGb3, lyso-ene-Gb3.…”

confidence: 99%

“…1 Nonlabeled lysoGb3 was synthesized as previously described (12 ). The synthesis of [5,6,7,8,9] 13 C 5 -labeled lysoGb3 was accomplished as depicted in the scheme in the online Supplemental Data file. Key to the synthetic scheme was the preparation of [5,6,7,8,9]-13 C 5 -erythro-sphingosine 10, which was accomplished as follows (for full experimental and analytical details see the online Supplemental Data).…”

Section: Patient Samplesmentioning

confidence: 99%

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Quantification of Globotriaosylsphingosine in Plasma and Urine of Fabry Patients by Stable Isotope Ultraperformance Liquid Chromatography–Tandem Mass Spectrometry

Gold

Mirzaian²,

Dekker³

et al. 2013

Clinical Chemistry

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BACKGROUND Biochemical markers that accurately reflect the severity and progression of disease in patients with Fabry disease and their response to treatment are urgently needed. Globotriaosylsphingosine, also called lysoglobotriaosylceramide (lysoGb3), is a promising candidate biomarker. METHODS We synthesized lysoGb3 and isotope-labeled [5,6,7,8,9] 13C5-lysoGb3 (internal standard). After addition of the internal standard to 25 μL plasma or 400 μL urine from patients with Fabry disease and healthy controls, samples were extracted with organic solvents and the lysoGb3 concentration was quantified by UPLC-ESI-MS/MS (ultraperformance liquid chromatography–electrospray ionization–tandem mass spectrometry). Calibration curves were constructed with control plasma and urine supplemented with lysoGb3. In addition to lysoGb3, lyso-ene-Gb3 was quantified. Quantification was achieved by multiple reaction monitoring of the transitions m/z 786.4 > 282.3 [M+H]+ for lysoGb3, m/z 791.4 > 287.3 [M+H]+ for [5,6,7,8,9] 13C5-lysoGb3, and 784.4 > 280.3 [M+H]+ for lyso-ene-Gb3. RESULTS The mean (SD) plasma lysoGb3 concentration from 10 classically affected Fabry hemizygotes was 94.4 (25.8) pmol/mL (range 52.7–136.8 pmol/mL), from 10 classically affected Fabry heterozygotes 9.6 (5.8) pmol/mL (range 4.1–23.5 pmol/mL), and from 20 healthy controls 0.4 (0.1) pmol/mL (range 0.3–0.5 pmol/mL). Lyso-ene-Gb3 concentrations were 10%–25% of total lysoGb3. The urine concentration of lysoGb3 was 40–480 times lower than in corresponding plasma samples. Lyso-ene-Gb3 concentrations in urine were comparable or even higher than the corresponding lysoGb3 concentrations. CONCLUSIONS This assay for the quantification of lysoGb3 and lyso-ene-Gb3 in human plasma and urine samples will be an important tool in the diagnosis of Fabry disease and for monitoring the effect of enzyme replacement therapy in patients with Fabry disease.

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“…They could show that lyso-Gb3 was elevated in patients with classical Fabry disease. Although the pathophysiological role of lyso-Gb3 in Fabry disease is not elucidated and mechanisms in Fabry organ complications involve multiple mechanisms beyond lyso-Gb3 (Schiffmann 2009;Auray-Blais et al 2010;Brakch et al 2010), the results of the study by Aerts et al suggested that lyso-Gb3 plays an important role as a factor in the pathogenesis and progression of the disease (Aerts et al 2008). Moreover, the same group also demonstrated little to normal values in atypical mutations (van Breemen et al 2011).…”

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confidence: 99%

Lyso-Gb3 Indicates that the Alpha-Galactosidase A Mutation D313Y is not Clinically Relevant for Fabry Disease

et al. 2012

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The X-chromosomal-linked lysosomal storage disorder Fabry disease can lead to life-threatening manifestations. The pathological significance of the Fabry mutation D313Y is doubted, because, in general, D313Y patients do not present clinical manifestations conformable with Fabry disease. This is in contrast to the analysis of the alphagalactosidase A activity, which is reduced in D313Y patients. We report a comprehensive clinical, biochemical and molecular genetic analysis of two patients with a D313Y mutation. The alpha-galactosidase A activity was reduced in both patients. No Fabry symptoms or Fabry organ involvement was detected in these patients. The new biomarker lyso-Gb3, severely increased in classical Fabry patients, was determined and in both patients lyso-Gb3 was below the average of a normal population.Our data for the first time not only clinically but also biochemically supports the hypothesis that the D313Y mutation is not a classical one, but a rare variant mutation.

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How well does urinary lyso-Gb3 function as a biomarker in Fabry disease?

Cited by 92 publications

References 29 publications

A Distinct Urinary Biomarker Pattern Characteristic of Female Fabry Patients That Mirrors Response to Enzyme Replacement Therapy

A Distinct Urinary Biomarker Pattern Characteristic of Female Fabry Patients That Mirrors Response to Enzyme Replacement Therapy

Quantification of Globotriaosylsphingosine in Plasma and Urine of Fabry Patients by Stable Isotope Ultraperformance Liquid Chromatography–Tandem Mass Spectrometry

Lyso-Gb3 Indicates that the Alpha-Galactosidase A Mutation D313Y is not Clinically Relevant for Fabry Disease

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