title: Phenotypical characterization of α-galactosidase A gene mutations identified in a large Fabry disease screening program in stroke in the young.
abstract: OBJECTIVE
  In the Belgian Fabry Study (BeFaS), the prevalence of Fabry disease was assessed in 1000 young patients presenting with stroke, unexplained white matter lesions or vertebrobasilar dolichoectasia. The results of the BeFaS suggested that Fabry disease may play a role in up to 1% of young patients presenting with cerebrovascular disease. However, the clinical relevance was unclear in all cases. We report on detailed phenotyping in subjects identified with α-galactosidase A (α-Gal A) enzyme deficiency or GLA mutations identified in the BeFaS (n=10), and on the results of family screening in this population.
  
  
  METHODS
  Family screening was performed to identify additional mutation carriers. Biochemical and/or clinical evaluation of all subjects (BeFaS index patients and relatives carrying a GLA mutation) was performed.
  
  
  RESULTS
  Genetic family screening revealed 18 additional GLA mutation carriers. Bloodspot α-Gal A enzyme activity was normal in all GLA mutation carriers, even in 2 males with the p.A143T mutation. Plasma Gb3 and lyso-Gb3 levels were normal in all subjects. Elevated Gb3 in urine was detected in 2 subjects. Some classic clinical signs of Fabry disease, like angiokeratoma or cornea verticillata, could not be detected in our population. Cardiac symptoms of Fabry disease were found in 6 out of 10 p.A143T carriers. No signs of cerebrovascular disease were found in the relatives with a GLA mutation.
  
  
  CONCLUSIONS
  We could not identify mutations causing the classical clinical phenotype of Fabry disease in our cerebrovascular disease population. Enzyme activity analysis in bloodspots and plasma may fail to identify late-onset variants of Fabry disease. We recommend genetic testing when an atypical, late-onset variant of Fabry disease is suspected in a male cerebrovascular disease patient. However, this may lead to the identification of non-disease causing or controversial genetic variants.
authors.affiliation: Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.
authors.forename: Isabel
authors.initials: I
authors.lastname: De Brabander
authors.forename: Laetitia
authors.initials: L
authors.lastname: Yperzeele
authors.forename: Chantal
authors.initials: C
authors.lastname: Ceuterick-De Groote
authors.forename: Raf
authors.initials: R
authors.lastname: Brouns
authors.forename: Robert
authors.initials: R
authors.lastname: Baker
authors.forename: Shibeshih
authors.initials: S
authors.lastname: Belachew
authors.forename: Jean
authors.initials: J
authors.lastname: Delbecq
authors.forename: Gilles
authors.initials: G
authors.lastname: De Keulenaer
authors.forename: Sophie
authors.initials: S
authors.lastname: Dethy
authors.forename: François
authors.initials: F
authors.lastname: Eyskens
authors.forename: Arnaud
authors.initials: A
authors.lastname: Fumal
authors.forename: Dimitri
authors.initials: D
authors.lastname: Hemelsoet
authors.forename: Derralynn
authors.initials: D
authors.lastname: Hughes
authors.forename: Sandrine
authors.initials: S
authors.lastname: Jeangette
authors.forename: Dirk
authors.initials: D
authors.lastname: Nuytten
authors.forename: Patricia
authors.initials: P
authors.lastname: Redondo
authors.forename: Bernard
authors.initials: B
authors.lastname: Sadzot
authors.forename: Christian
authors.initials: C
authors.lastname: Sindic
authors.forename: Rishi
authors.initials: R
authors.lastname: Sheorajpanday
authors.forename: Vincent
authors.initials: V
authors.lastname: Thijs
authors.forename: Christine
authors.initials: C
authors.lastname: Van Broeckhoven
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
mesh_terms: D000328:Adult; D001530:Belgium / Q000453:epidemiology; D004452:Echocardiography; D004562:Electrocardiography; D000795:Fabry Disease / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D006017:Glycolipids / Q000097:blood / Q000652:urine; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics* / Q000502:physiology; D010641:Phenotype; D012867:Skin / Q000473:pathology; D013107:Sphingolipids / Q000097:blood / Q000652:urine; D020521:Stroke / Q000453:epidemiology / Q000235:genetics*; D014281:Trihexosylceramides / Q000097:blood / Q000652:urine; D014715:Vertebrobasilar Insufficiency / Q000473:pathology; D055815:Young Adult; D000519:alpha-Galactosidase / Q000097:blood / Q000235:genetics* / Q000652:urine
chemical_list: D006017:Glycolipids; D013107:Sphingolipids; D014281:Trihexosylceramides; C063288:globotriaosyl lysosphingolipid; C018549:globotriaosylceramide; D000519:alpha-Galactosidase