The validation of pharmacogenetics for the identification of Fabry patients to be treated with migalastat

Genet Med. 2017 Apr;19(4):430-438. doi: 10.1038/gim.2016.122. Epub 2016 Sep 22.


Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Trial registration: NCT00214500 NCT00283959 NCT00283933 NCT00304512 NCT00925301 NCT01218659.

MeSH terms

  • 1-Deoxynojirimycin / administration & dosage
  • 1-Deoxynojirimycin / analogs & derivatives*
  • 1-Deoxynojirimycin / pharmacology
  • Biological Assay
  • Cell Line
  • Clinical Trials, Phase II as Topic
  • Clinical Trials, Phase III as Topic
  • Fabry Disease / drug therapy
  • Fabry Disease / genetics*
  • Female
  • HEK293 Cells
  • Humans
  • Leukocytes / drug effects
  • Leukocytes / enzymology
  • Male
  • Mutation*
  • Predictive Value of Tests
  • Validation Studies as Topic
  • alpha-Galactosidase / genetics*


  • 1-Deoxynojirimycin
  • migalastat
  • GLA protein, human
  • alpha-Galactosidase

Associated data