title: Plasma globotriaosylsphingosine in relation to phenotypes of Fabry disease.
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.
authors.affiliation: Division Endocrinology and Metabolism, Department of Internal Medicine, Amsterdam lysosome center 'Sphinx', Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Bouwien E
authors.initials: BE
authors.lastname: Smid
authors.affiliation: Division Endocrinology and Metabolism, Department of Internal Medicine, Amsterdam lysosome center 'Sphinx', Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Linda
authors.initials: L
authors.lastname: van der Tol
authors.affiliation: Division Endocrinology and Metabolism, Department of Internal Medicine, Amsterdam lysosome center 'Sphinx', Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Biegstraaten
authors.affiliation: Division Endocrinology and Metabolism, Department of Internal Medicine, Amsterdam lysosome center 'Sphinx', Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Gabor E
authors.initials: GE
authors.lastname: Linthorst
authors.affiliation: Division Endocrinology and Metabolism, Department of Internal Medicine, Amsterdam lysosome center 'Sphinx', Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Carla E M
authors.initials: CE
authors.lastname: Hollak
authors.affiliation: Laboratory of Genetic Metabolic Diseases, Amsterdam lysosome center 'Sphinx', Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ben J H M
authors.initials: BJ
authors.lastname: Poorthuis
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000795:Fabry Disease / Q000097:blood* / Q000235:genetics; D005260:Female; D006017:Glycolipids / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D013107:Sphingolipids / Q000097:blood*; D014281:Trihexosylceramides / Q000097:blood; D055815:Young Adult; D000519:alpha-Galactosidase / Q000097:blood
chemical_list: D006017:Glycolipids; D013107:Sphingolipids; D014281:Trihexosylceramides; C063288:globotriaosyl lysosphingolipid; C018549:globotriaosylceramide; D000519:alpha-Galactosidase
keywords: Diagnosis; Fabry disease; Genetic screening; Globotriaosylsphingosine; Phenotype