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

J Inherit Metab Dis. 2020 Mar;43(2):326-333. doi: 10.1002/jimd.12167. Epub 2019 Sep 30.

PMID: 31449323

Albina Nowak, Uyen Huynh-Do, Pierre-Alexandre Krayenbuehl, Felix Beuschlein, Raphael Schiffmann, Frédéric Barbey

Summary: The frequency of amenable mutations, related to phenotype, in a population of adult patients with Fabry Disease (FD) in Switzerland is investigated in this research. Further studies are needed to determine the long-term effects of migalastat therapy based on the enzyme activity achieved in different amenable mutations.

Abstract

Objective: Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by a lack of the enzyme α-galactosidase A (α-Gal A). The progressive accumulation of globotriaosylceramide leads to life-threatening consequences such as renal, cardiac, and cerebrovascular disorders. In individuals with amenable mutations, the pharmacological chaperone migalastat was recently approved as an alternative to enzyme replacement therapy. The frequency of amenable mutations, related to phenotype, in a population of adult patients with FD in Switzerland is investigated in this research.

Methods: This study included 170 adult patients (n = 64 males) from 46 independent pedigrees with 39 different identified mutations over the last 59 years. In total, 68% of the participants possessed the classic phenotype, whereas 48 percent met the current amenability criteria.

Results: Migalastat was withdrawn in 2/11 (18%) patients: the only male classic case, because of lack of efficacy based on lyso-Gb3 levels, and 1 patient with a benign variant.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.F113 L; 43% in leucocytes vs 36% in HEK-cells for p.N215S, 24-30% in leucocytes vs 96% in HEK-cells for S238 N).

Conclusion: This study discovered a rather high proportion of individuals with amenable GLA mutations in this national cohort, however, the extent of amenability was heterogeneous: the higher the residual α-Gal A activity, the higher the chaperone effect. Further studies are needed to determine the long-term effects of migalastat therapy based on the enzyme activity achieved in different amenable mutations.