A Metabolomic Study To Identify New Globotriaosyl­ceramide-Related Biomarkers in the Plasma of Fabry Disease Patients

Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of the enzyme α-galactosidase A, which results in the progressive accumulation of glycosphingolipids. In addition to the two biomarkers, globotriaosyl­ceramide (Gb₃) and globotriaosyl­sphingosine (lyso-Gb₃), which are routinely used for detection and high-risk screening of Fabry disease patients, novel urinary Gb₃-related isoforms/analogues as well as newly defined lyso-Gb₃ analogues in plasma and urine from Fabry patients have recently been described by our group. The aim of this study was to extend our recent analyses to identify and evaluate new potential Gb₃-related biomarkers in the plasma of untreated male Fabry disease patients using a mass spectrometry metabolomic approach. A multivariate statistical analysis revealed five Gb₃-related novel biomarkers in the plasma of male Fabry patients. Three of these new biomarkers correspond to Gb₃, which has an extra double bond on the sphingosine with C16:0, C18:0, and C22:1 fatty acid chains. The fourth biomarker corresponds to a mixture of two structural isomers, the first with a d16:1 sphingosine and a C16:0 fatty acid and the second with a d18:1 sphingosine and a C14:0 fatty acid. To our knowledge, it is the first time that a Gb₃ analogue with a d16:1 sphingosine moiety has been reported. In addition, this Gb₃ analogue was also present in its methylated form. These biomarkers are part of a metabolic profile that may provide insight into the pathophysiology of Fabry disease

The Identification of New Biomarkers for Identifying and Monitoring Kidney Disease and Their Translation into a Rapid Mass Spectrometry-Based Test: Evidence of Presymptomatic Kidney Disease in Pediatric Fabry and Type‑I Diabetic Patients

Using label-free quantative proteomics, we have identified 2 potential protein biomarkers that indicate presymptomatic kidney disease in the urine of pediatric patients with type-I diabetes and Fabry disease (<i>n</i> = 20). Prosaposin and GM₂ activator protein (GM₂AP) were observed to be elevated in the urine of these patient groups compared to age- and sex-matched controls. These findings were validated by development of a rapid MRM-based tandem mass spectrometry test. Prosaposin was observed to be both significantly elevated in the urine of patients with Fabry disease compared to controls (<i>p</i> = 0.02) and reduced after 12 months enzyme replacement therapy (ERT, <i>p</i> = 0.01). Similarly, GM₂AP concentrations were observed to be significantly higher compared to controls in the diabetic group (<i>p</i> = 0.049) and the pretreatment Fabry group (<i>p</i> = 0.003). In addition, this observed to be reduced significantly in the Fabry group following 12 months of ERT (<i>p</i> = 0.01). The process of detection of the biomarkers, development into a test and implications for monitoring patients and treatment are discussed