Bouwien E Smid1, Linda van der Tol1, Marieke Biegstraaten1, Gabor E Linthorst1, Carla E M Hollak1, Ben J H M Poorthuis2. 1. Division Endocrinology and Metabolism, Department of Internal Medicine, Amsterdam lysosome center 'Sphinx', Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 2. Laboratory of Genetic Metabolic Diseases, Amsterdam lysosome center 'Sphinx', Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Abstract
BACKGROUND: Fabry disease (FD), a lysosomal storage disorder caused by α-galactosidase A (GLA) gene variants, has a heterogeneous phenotype. GLA variants can lead to classical FD, an attenuated non-classical phenotype, or no disease at all. This study investigates the value of plasma globotriaosylsphingosine (lysoGb3) to distinguish between these groups. This is of particular importance in the diagnosis of individuals with a GLA variant and an uncertain diagnosis of FD, lacking characteristic features of classical FD. METHODS: Subjects with GLA variants were grouped as classical, non-classical, uncertain or no FD, using strict phenotypical, biochemical and histological criteria. Plasma lysoGb3 was assessed by LC/MS/MS (normal ≤ 0.6 nmol/L). RESULTS: 154 subjects were grouped into classical (38 males (M), 66 females (F)), non-classical (13 M, 14 F), uncertain (5M, 9 F) or no FD (6M, 3F). All subjects with a classical phenotype had elevated lysoGb3 values (M: range 45-150, F: 1.5-41.5). LysoGb3 values in patients with a non-classical phenotype (M: 1.3-35.7, F: 0.5-2.0) were different from healthy controls (M: p<0.01, F: p<0.05), but females overlapped with controls. In the no-FD group, lysoGb3 was normal. CONCLUSIONS: LysoGb3 is a reliable diagnostic tool to discern classical FD from subjects without FD. This study suggests that the same applies to patients with a non-classical phenotype. LysoGb3 values of female patients overlap with controls. Consequently, in uncertain cases, increased lysoGb3 values are very suggestive for FD, but normal values cannot exclude FD. Confirmation in larger cohorts and data on the specificity of small lysoGb3 increases are necessary. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
BACKGROUND:Fabry disease (FD), a lysosomal storage disorder caused by α-galactosidase A (GLA) gene variants, has a heterogeneous phenotype. GLA variants can lead to classical FD, an attenuated non-classical phenotype, or no disease at all. This study investigates the value of plasma globotriaosylsphingosine (lysoGb3) to distinguish between these groups. This is of particular importance in the diagnosis of individuals with a GLA variant and an uncertain diagnosis of FD, lacking characteristic features of classical FD. METHODS: Subjects with GLA variants were grouped as classical, non-classical, uncertain or no FD, using strict phenotypical, biochemical and histological criteria. Plasma lysoGb3 was assessed by LC/MS/MS (normal ≤ 0.6 nmol/L). RESULTS: 154 subjects were grouped into classical (38 males (M), 66 females (F)), non-classical (13 M, 14 F), uncertain (5M, 9 F) or no FD (6M, 3F). All subjects with a classical phenotype had elevated lysoGb3 values (M: range 45-150, F: 1.5-41.5). LysoGb3 values in patients with a non-classical phenotype (M: 1.3-35.7, F: 0.5-2.0) were different from healthy controls (M: p<0.01, F: p<0.05), but females overlapped with controls. In the no-FD group, lysoGb3 was normal. CONCLUSIONS: LysoGb3 is a reliable diagnostic tool to discern classical FD from subjects without FD. This study suggests that the same applies to patients with a non-classical phenotype. LysoGb3 values of female patients overlap with controls. Consequently, in uncertain cases, increased lysoGb3 values are very suggestive for FD, but normal values cannot exclude FD. Confirmation in larger cohorts and data on the specificity of small lysoGb3 increases are necessary. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Authors: C Simoncini; S Torri; V Montano; L Chico; F Gruosso; A Tuttolomondo; A Pinto; I Simonetta; V Cianci; A Salviati; V Vicenzi; G Marchi; D Girelli; D Concolino; S Sestito; M Zedde; G Siciliano; Michelangelo Mancuso Journal: J Neurol Date: 2020-07-27 Impact factor: 4.849
Authors: Luigi Pianese; Antonio Fortunato; Serena Silvestri; Francesco G Solano; Alberto Burlina; Alessandro P Burlina; Michele Ragno Journal: Neurol Sci Date: 2019-02-14 Impact factor: 3.307
Authors: Maarten Arends; Christoph Wanner; Derralynn Hughes; Atul Mehta; Daniel Oder; Oliver T Watkinson; Perry M Elliott; Gabor E Linthorst; Frits A Wijburg; Marieke Biegstraaten; Carla E Hollak Journal: J Am Soc Nephrol Date: 2016-12-15 Impact factor: 10.121
Authors: Rannveig Skrunes; Camilla Tøndel; Sabine Leh; Kristin Kampevold Larsen; Gunnar Houge; Einar Skulstad Davidsen; Carla Hollak; André B P van Kuilenburg; Frédéric M Vaz; Einar Svarstad Journal: Clin J Am Soc Nephrol Date: 2017-06-16 Impact factor: 8.237
Authors: A Bersano; M Kraemer; A Burlina; M Mancuso; J Finsterer; S Sacco; C Salvarani; L Caputi; H Chabriat; S Lesnik Oberstein; A Federico; E Tournier Lasserve; D Hunt; M Dichgans; M Arnold; S Debette; H S Markus Journal: J Neurol Date: 2020-04-21 Impact factor: 4.849
Authors: Susana Ferreira; Christiane Auray-Blais; Michel Boutin; Pamela Lavoie; José Pedro Nunes; Elisabete Martins; Scott Garman; João Paulo Oliveira Journal: Clin Chim Acta Date: 2015-06-09 Impact factor: 3.786