title: Fabry disease: a new approach for the screening of females in high-risk groups.
abstract: OBJECTIVE
  Fabry disease (FD) is a rare X-linked inborn error of metabolism caused by deficient activity of lysosomal α-galactosidase A (α-GAL). Due to random X inactivation, α-GAL activity in heterozygous females ranges from very low to overlapping normal values. Determining this specific range and altering assays cutoffs could become a valuable tool for minimizing the need in DNA sequencing for screening of all potential carriers. Therefore, the aim of this study was to establish the range of enzyme in dried blood spots (DBS), plasma and leukocytes that suggests carrier status for FD.
  
  
  METHODS
  α-GAL gene was sequenced in 453 women with clinical suspicion and/or positive family history of FD. This data was compared to the α-GAL activity measured in DBS (dried blood spots) and/or plasma and/or leukocytes.
  
  
  RESULTS
  About 12% of the samples had pathogenic mutations (c.30_32delG, c.718_719delAA, p.R118C, p.S126G, p.Y152X, p.A156D, p.C202Y, p.N215S, p.P259R, p.D264Y, p.V269M, p.R342Q and p.R356W). When compared to genotype, DBS was the least reliable biochemical test for screening, with very low specificity. Plasma and leukocyte activities presented high AUC in ROC curve analysis, both over 84%. When cutoffs were altered to identify all carriers, leukocyte specificity was higher than that of plasma (35.2% and 27.6%, respectively). Moderated correlation and agreement coefficients were found between them, which reinforces the need for using both data combined.
  
  
  CONCLUSIONS
  A combined approach involving plasma and leukocyte α-GAL activities, with distinct cutoffs for men and women, could represent a more accurate, faster and less expensive tool to screen women for FD in high-risk groups in middle- and low-income countries.
authors.affiliation: Post-Graduation Program on Genetics and Molecular Biology, UFRGS, Porto Alegre, RS, Brazil; Gene Therapy Center, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Pasqualim
authors.affiliation: Post-Graduation Program on Genetics and Molecular Biology, UFRGS, Porto Alegre, RS, Brazil; Gene Therapy Center, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Laura
authors.initials: L
authors.lastname: Simon
authors.affiliation: Gene Therapy Center, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Sperb-Ludwig
authors.affiliation: Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Maira Graef
authors.initials: MG
authors.lastname: Burin
authors.affiliation: Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Kristiane
authors.initials: K
authors.lastname: Michelin-Tirelli
authors.affiliation: Post-Graduation Program on Genetics and Molecular Biology, UFRGS, Porto Alegre, RS, Brazil; Gene Therapy Center, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil; Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil; Department of Genetics, UFRGS, Porto Alegre, RS, Brazil; INAGEMP, Porto Alegre, RS, Brazil. Electronic address: rgiugliani@hcpa.ufrgs.br.
authors.forename: Roberto
authors.initials: R
authors.lastname: Giugliani
authors.affiliation: Post-Graduation Program on Genetics and Molecular Biology, UFRGS, Porto Alegre, RS, Brazil; Gene Therapy Center, Experimental Research Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil.
authors.forename: Ursula
authors.initials: U
authors.lastname: Matte
mesh_terms: D000795:Fabry Disease / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics; D005260:Female; D006580:Genetic Carrier Screening; D005838:Genotype; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D009154:Mutation; D010949:Plasma / Q000378:metabolism; D000519:alpha-Galactosidase / Q000235:genetics
chemical_list: D000519:alpha-Galactosidase
keywords: Fabry disease; Molecular diagnosis; Screening; α-GAL activity