Fabry disease genotype, phenotype, and migalastat amenability: Insights from a national cohort.

Abstract

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by α-galactosidase A (α-Gal A) deficiency. The progressive accumulation of globotriaosylceramide results in life-threatening complications, including renal, cardiac, and cerebrovascular diseases. The pharmacological chaperone migalastat was recently approved as an alternative to enzyme replacement therapy in patients with amenable mutations. In this article, we investigate the proportion of amenable mutations, related to phenotype, in a population of adult patients with FD in Switzerland. This study included 170 adult patients (n = 64 males) from 46 independent pedigrees with 39 different identified mutations over the last 59 years. Overall, 68% had the classic phenotype and 48% fulfilled the current amenability criteria. Migalastat was stopped in 2/11 (18%) patients: the only male classic patient, because of lack of efficacy based on lyso-Gb3 levels, and one patient with a benign variant. In males, the achieved enzyme activities in peripheral leucocytes under migalastat treatment differed from the activities in HEK-cells after incubation with migalastat (eg, 33% in PL vs 41% HEK-cells for p.F113L; 43% in leucocytes vs 36% in HEK-cells for p.N215S, 24-30% in leucocytes vs 96% in HEK-cells for S238N). In this national cohort, we found a relatively high proportion of patients with amenable GLA mutations, which, however, had heterogeneous extent of amenability: the higher the residual α-Gal A activity, the higher the chaperone effect. Further studies are required to investigate the long-term benefits of migalastat therapy depending on the achieved enzyme activities in different amenable mutations.

• Authors: Albina Nowak, Uyen Huynh-Do, Pierre-Alexandre Krayenbuehl, Felix Beuschlein, Raphael Schiffmann, Frédéric Barbey
• Journal: Journal of inherited metabolic disease (J Inherit Metab Dis) Vol. 43 Issue 2 Pg. 326-333 (03 2020) ISSN: 1573-2665 [Electronic] United States
• PMID: 31449323 (Publication Type: Journal Article, Multicenter Study)
• Copyright: © 2019 SSIEM.

Chemical References

• 1-Deoxynojirimycin
• migalastat
• alpha-Galactosidase

Topics

• 1-Deoxynojirimycin (analogs & derivatives, pharmacology)
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Biological Assay (standards)
• Fabry Disease (drug therapy, genetics)
• Female
• Genetic Variation
• Genotype
• HEK293 Cells
• Humans
• Male
• Middle Aged
• Mutation
• Phenotype
• Prospective Studies
• Switzerland
• Young Adult
• alpha-Galactosidase (genetics)