title: Multiplex tandem mass spectrometry analysis of novel plasma lyso-Gb₃-related analogues in Fabry disease.
abstract: Fabry disease is a multisystemic, X-linked lysosomal storage disorder caused by a deficit in α-galactosidase A enzyme activity leading to glycosphingolipid accumulation, mainly globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3). Recent metabolomic studies have led to the discovery of novel biomarkers related to lyso-Gb3 in plasma and urine. These biomarkers show modifications of the sphingosine moiety of the lyso-Gb3 molecule. The objectives of this study were to develop and validate a liquid chromatography-tandem mass spectrometry method for the relative quantification of novel plasma lyso-Gb3-related analogues, to evaluate their levels in plasma of 74 Fabry patients and 41 healthy controls and to correlate these results with patient gender, enzyme replacement therapy treatment, and lyso-Gb3 analogue levels previously measured in urine for the same patients. As expected, the concentrations of lyso-Gb3 and its related analogues in plasma are higher in Fabry males compared to Fabry females and higher for untreated males compared to treated males. The concentration of lyso-Gb3 and its related analogues in plasma decrease significantly after the beginning of enzyme replacement therapy (ERT) treatment and remain stable for 30 months of monitored therapy in a Fabry male. In plasma, lyso-Gb3 is significantly more abundant than its related analogues, which differs from urine where the majority of the lyso-Gb3 analogues are more increased than lyso-Gb3 itself. In contrast to urine, the relative distribution of lyso-Gb3 and its analogues in plasma is similar from one individual to another in the same group of Fabry patients, irrespective of ERT. This study revealed a large discrepancy between the relative abundance of lyso-Gb3 and its analogues in urine and plasma. Further studies will thus be needed to better understand the metabolic relationship between plasma and urine lyso-Gb3-related biomarkers.
authors.affiliation: Service of Genetics, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke , 3001 12th Avenue North, Sherbrooke, Québec J1H 5N4, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Boutin
authors.forename: Christiane
authors.initials: C
authors.lastname: Auray-Blais
mesh_terms: D002853:Chromatography, Liquid; D000795:Fabry Disease / Q000097:blood*; D006017:Glycolipids / Q000097:blood* / Q000737:chemistry; D006801:Humans; D013107:Sphingolipids / Q000097:blood* / Q000737:chemistry; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D006017:Glycolipids; D013107:Sphingolipids; C063288:globotriaosyl lysosphingolipid