title: The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat.
abstract: Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene. Migalastat, a pharmacological chaperone, binds to specific mutant forms of α-galactosidase A to restore lysosomal activity.
  
  
  
  A pharmacogenetic assay was used to identify the α-galactosidase A mutant forms amenable to migalastat. Six hundred Fabry disease-causing mutations were expressed in HEK-293 (HEK) cells; increases in α-galactosidase A activity were measured by a good laboratory practice (GLP)-validated assay (GLP HEK/Migalastat Amenability Assay). The predictive value of the assay was assessed based on pharmacodynamic responses to migalastat in phase II and III clinical studies.
  
  
  
  Comparison of the GLP HEK assay results in in vivo white blood cell α-galactosidase A responses to migalastat in male patients showed high sensitivity, specificity, and positive and negative predictive values (≥0.875). GLP HEK assay results were also predictive of decreases in kidney globotriaosylceramide in males and plasma globotriaosylsphingosine in males and females. The clinical study subset of amenable mutations (n = 51) was representative of all 268 amenable mutations identified by the GLP HEK assay.
  
  
  
  The GLP HEK assay is a clinically validated method of identifying male and female Fabry patients for treatment with migalastat.Genet Med 19 4, 430-438.
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, USA.
authors.forename: Elfrida R
authors.initials: ER
authors.lastname: Benjamin
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, USA.
authors.forename: Maria Cecilia
authors.identifier: 0000-0002-4994-7065
authors.initials: MC
authors.lastname: Della Valle
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, USA.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Wu
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, USA.
authors.forename: Evan
authors.initials: E
authors.lastname: Katz
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, USA.
authors.forename: Farhana
authors.initials: F
authors.lastname: Pruthi
authors.affiliation: Cambridge Biomedical, Boston, Massachusetts, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bond
authors.affiliation: Cambridge Biomedical, Boston, Massachusetts, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bronfin
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, USA.
authors.forename: Hadis
authors.identifier: 0000-0001-5727-7551
authors.initials: H
authors.lastname: Williams
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Yu
authors.affiliation: Hôpital du Sacré-Coeur, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Bichet
authors.affiliation: Division of Medical Genetics, University of Versailles, University Paris-Saclay, Montigny, France.
authors.forename: Dominique P
authors.identifier: 0000-0002-8355-007X
authors.initials: DP
authors.lastname: Germain
authors.affiliation: Medical Genetics Service, HCPA/UFRGS, Porto Alegre, Brazil.
authors.forename: Roberto
authors.identifier: 0000-0001-9655-3686
authors.initials: R
authors.lastname: Giugliani
authors.affiliation: Royal Free Campus, University College London, London, UK.
authors.forename: Derralynn
authors.identifier: 0000-0003-4531-9173
authors.initials: D
authors.lastname: Hughes
authors.affiliation: Baylor Research Institute, Dallas, Texas, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Schiffmann
authors.affiliation: Department of Human Genetics, Emory Univ, Atlanta, Georgia, USA.
authors.forename: William R
authors.identifier: 0000-0002-0325-0377
authors.initials: WR
authors.lastname: Wilcox
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, USA.
authors.forename: John
authors.initials: J
authors.lastname: Kirk
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, USA.
authors.forename: Jay
authors.identifier: 0000-0001-8562-9104
authors.initials: J
authors.lastname: Barth
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, USA.|Current address: The Parkinson's Institute and Clinical Center, Sunnyvale, California, USA.
authors.forename: Carrolee
authors.initials: C
authors.lastname: Barlow
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Valenzano
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, USA.
authors.forename: Jeff
authors.identifier: 0000-0002-8751-7015
authors.initials: J
authors.lastname: Castelli
authors.affiliation: Amicus Therapeutics, Cranbury, New Jersey, USA.|Current address: TranscripTx, Inc., Sunnyvale, California, USA.
authors.forename: David J
authors.identifier: 0000-0001-9560-0196
authors.initials: DJ
authors.lastname: Lockhart
mesh_terms: D017485:1-Deoxynojirimycin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D001681:Biological Assay; D002460:Cell Line; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D000795:Fabry Disease / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009154:Mutation; D011237:Predictive Value of Tests; D054928:Validation Studies as Topic; D000519:alpha-Galactosidase / Q000235:genetics*
chemical_list: D017485:1-Deoxynojirimycin; C090092:migalastat; C576330:GLA protein, human; D000519:alpha-Galactosidase