title: Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant.
abstract: Fabry disease (FD) is an X-linked multisystemic disorder with a heterogeneous phenotype. Especially atypical or late-onset type 2 phenotypes present a therapeutical dilemma.
  
  
  
  To determine the clinical impact of the alpha-Galactosidase A (GLA) p.A143T/ c.427G > A variation, we retrospectively analyzed 25 p.A143T patients in comparison to 58 FD patients with other missense mutations.
  
  
  
  p.A143T patients suffering from stroke/ transient ischemic attacks had slightly decreased residual GLA activities, and/or increased lyso-Gb3 levels, suspecting FD. However, most male p.A143T patients presented with significant residual GLA activity (~50 % of reference), which was associated with normal lyso-Gb3 levels. Additionally, p.A143T patients showed less severe FD-typical symptoms and absent FD-typical renal and cardiac involvement in comparison to FD patients with other missense mutations. Two tested female p.A143T patients with stroke/TIA did not show skewed X chromosome inactivation. No accumulation of neurologic events in family members of p.A143T patients with stroke/transient ischemic attacks was observed.
  
  
  
  We conclude that GLA p.A143T seems to be most likely a neutral variant or a possible modifier instead of a disease-causing mutation. Therefore, we suggest that p.A143T patients with stroke/transient ischemic attacks of unknown etiology should be further evaluated, since the diagnosis of FD is not probable and subsequent ERT or chaperone treatment should not be an unreflected option.
authors.affiliation: Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Albert-Schweitzer-Campus 1, D-48149, Muenster, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Lenders
authors.affiliation: Department of Medicine, Divisions of Cardiology and Nephrology, Comprehensive Heart Failure Center, Fabry Center for Interdisciplinary Therapy (FAZIT), University of Wuerzburg, Wuerzburg, Germany.|Katharinen-Hospital Unna, Unna, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Weidemann
authors.affiliation: Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Kurschat
authors.affiliation: Department of Medicine, Division of Nephrology, University Hospital Charité, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Sima
authors.initials: S
authors.lastname: Canaan-Kühl
authors.affiliation: Department of Neurology, University Hospital Muenster, Muenster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Duning
authors.affiliation: Department of Cardiovascular Medicine, Division of Cardiology, University Hospital Muenster, Muenster, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Stypmann
authors.affiliation: Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, University Hospital Muenster, Muenster, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Schmitz
authors.affiliation: Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Albert-Schweitzer-Campus 1, D-48149, Muenster, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Reiermann
authors.affiliation: Department of Medicine, Divisions of Cardiology and Nephrology, Comprehensive Heart Failure Center, Fabry Center for Interdisciplinary Therapy (FAZIT), University of Wuerzburg, Wuerzburg, Germany.|Department of Pediatrics an Adolescence Medicine, University of Ulm, Ulm, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Krämer
authors.affiliation: Department of Medicine, Division of Cardiology, University Hospital Charité, Campus Virchow-Klinikum, Berlin, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Blaschke
authors.affiliation: Department of Medicine, Divisions of Cardiology and Nephrology, Comprehensive Heart Failure Center, Fabry Center for Interdisciplinary Therapy (FAZIT), University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wanner
authors.affiliation: Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease, University Hospital Muenster, Muenster, Germany.
authors.forename: Stefan-Martin
authors.initials: SM
authors.lastname: Brand
authors.affiliation: Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, Albert-Schweitzer-Campus 1, D-48149, Muenster, Germany. Eva.Brand@ukmuenster.de.
authors.forename: Eva
authors.initials: E
authors.lastname: Brand
mesh_terms: D000328:Adult; D000795:Fabry Disease / Q000201:enzymology* / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D002546:Ischemic Attack, Transient / Q000201:enzymology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D012189:Retrospective Studies; D020521:Stroke / Q000201:enzymology / Q000235:genetics; D000519:alpha-Galactosidase / Q000235:genetics*
chemical_list: D000519:alpha-Galactosidase
keywords: Fabry disease; GLA mutation; Genotype; Late-onset; Lyso-Gb3; Stroke; Variant of unknown significance