Fabry disease is a lysosomal storage disorder caused by mutations in the GLA gene that encodes for the lysosomal enzyme α-galactosidase A (α-Gal A). Reduced or absent α-Gal A activity leads to substrate accumulation and deleterious effects in multiple organs. Migalastat is a pharmacological chaperone that may stabilize the enzyme in specific GLA variants， considered amenable， assisting enzyme trafficking to lysosomes and thus increasing enzyme activity. Using a good laboratory practice (GLP)-validated human embryonic kidney cell (HEK)-based (GLP-HEK) amenability assay established during the clinical development of migalastat， approximately one-third of GLA variants are reported to be amenable to migala... More
Fabry disease is a lysosomal storage disorder caused by mutations in the GLA gene that encodes for the lysosomal enzyme α-galactosidase A (α-Gal A). Reduced or absent α-Gal A activity leads to substrate accumulation and deleterious effects in multiple organs. Migalastat is a pharmacological chaperone that may stabilize the enzyme in specific GLA variants， considered amenable， assisting enzyme trafficking to lysosomes and thus increasing enzyme activity. Using a good laboratory practice (GLP)-validated human embryonic kidney cell (HEK)-based (GLP-HEK) amenability assay established during the clinical development of migalastat， approximately one-third of GLA variants are reported to be amenable to migalastat. On the basis of this biochemical amenability， migalastat is approved for use in patients with specific GLA variants. In this study， the reproducibility of the amenability assay was assessed by evaluation of 59 GLA variants for α-Gal A activity in the presence and absence of migalastat. As for the GLP-HEK assay， variants were considered amenable when there was both an absolute increase in enzyme activity of ≥3% wild-type and a relative increase in enzyme activity ≥1.2 fold over baseline following incubation with migalastat. Six of the 59 variants tested here did not match the classification of amenability reported using the GLP-HEK assay. Linear regression and Bland-Altman analyses， comparing data from all variants with and without migalastat， provided additional evidence for a lack of assay reproducibility. Data from the GLP-HEK assay (and the resulting classification of amenability) can determine treatment strategy and， ultimately， patient outcomes， so discrepancies between amenability assay data could be a cause for concern for physicians managing patients with Fabry disease.
