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Aims: Anderson-Fabry disease (AFD) is an important X-linked metabolic disease resulting in progressive end-organ involvement, with cardiac disease being the dominant determinant of survival in a gender-dependent manner. Recent epidemiological screening for AFD suggests the prevalence is much higher than previously recognized, with estimates of 1:3000. Our aim was to discover novel plasma biomarker signatures in adult patients with AFD., Methods and Results: We used an unbiased proteomic screening approach to discover novel plasma biomarker signatures. In the discovery cohort of 46 subjects, 14 healthy controls and 32 patients with AFD, we used a mass spectrometry iTRAQ proteomic approach followed by multiple reaction monitoring (MRM) assays to identify biomarkers. Of the 38 protein groups discovered by iTRAQ, 18 already had existing MRM assays. Based on MRM, we identified an eight-protein biomarker panel (22 kDa protein, afamin, α1 antichymotrypsin, apolipoprotein E, β-Ala His dipeptidase, haemoglobin α-2, isoform 1 of sex hormone-binding globulin, and peroxiredoxin 2) that was very specific and sensitive for male AFD patients. In female AFD patients, we identified a nine-marker panel of proteins with only three proteins, apolipoprotein E, haemoglobin α-2, and peroxiredoxin 2, common to both genders, suggesting a gender-specific alteration in plasma biomarkers in patients with AFD. The biomarkers were validated in plasma samples from 48 subjects using MRM, and they performed inferiorly in patients with heart failure., Conclusions: We have identified gender-specific plasma protein biomarker panels that are specific and sensitive for the AFD phenotype. The gender-specific panels offer important insight into potential differences in pathophysiology and prognosis between males and females with AFD., (© 2015 The Authors. European Journal of Heart Failure © 2015 European Society of Cardiology.)

Background: Fabry disease is an X-linked lysosomal storage disorder affecting both males and females with tremendous genotypic/phenotypic variability. Concentrations of globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3)/related analogues were investigated in pediatric and adult Fabry cohorts. The aims of this study were to transfer and validate an HPLC-MS/MS methodology on a UPLC-MS/MS new generation platform, using an HPLC column, for urine analysis of treated and untreated pediatric and adult Fabry patients, to establish correlations between the excretion of Fabry biomarkers with gender, treatment, types of mutations, and to evaluate the biomarker reliability for early detection of pediatric Fabry patients., Method: A UPLC-MS/MS was used for biomarker analysis., Results: Reference values are presented for all biomarkers. Results show that gender strongly influences the excretion of each biomarker in the pediatric Fabry cohort, with females having lower urinary levels of all biomarkers. Urinary distribution of lyso-Gb3/related analogues in treated Fabry males was similar to the untreated and treated Fabry female groups in both children and adult cohorts. Children with the late-onset p.N215S mutation had normal urinary levels of Gb3, and lyso-Gb3 but abnormal levels of related analogues., Conclusions: In this study, Fabry males and most Fabry females would have been diagnosed using the urinary lyso-Gb3/related analogue profile., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Abstract: Background: Fabry disease is characterized by accumulation of glycosphingolipids, such as globotriaosylceramide (Gb3), in many tissues and body fluids. A novel plasma biomarker, globotriaosylsphingosine (lyso-Gb3), is increased in patients with the disease. Until now, lyso-Gb3 was not detectable in urine, possibly because of the presence of interfering compounds. Methods: We undertook to: 1) characterize lyso-Gb3 in urine; 2) develop a method to quantitate urinary lyso-Gb3 by mass spectrometry; 3) evaluate urinary lyso-Gb3 as a potential biomarker for Fabry disease; and 4) determine whether lyso-Gb3 is an inhibitor of α-galactosidase A activity. We analyzed urinary lyso-Gb3 from 83 Fabry patients and 77 healthy age-matched controls. Results: The intraday and interday bias and precision of the method were <15%. Increases in lyso-Gb3/creatinine correlated with the concentrations of Gb3 (r 2 =0.43), type of mutations (p =0.0006), gender (p <0.0001) and enzyme replacement therapy status (p =0.0012). Urine from healthy controls contained no detectable lyso-Gb3. Lyso-Gb3 did not inhibit GLA activity in dried blood spots. Increased urinary excretion of lyso-Gb3 of Fabry patients correlated well with a number of indicators of disease severity. Conclusion: Lyso-Gb3 is a reliable independent biomarker for clinically important characteristics of Fabry disease. [ABSTRACT FROM AUTHOR]