Fabry disease genotype, phenotype, and migalastat amenability: Insights from a national cohort.
1-Deoxynojirimycin
/ analogs & derivatives
Adolescent
Adult
Aged
Aged, 80 and over
Biological Assay
/ standards
Fabry Disease
/ drug therapy
Female
Genetic Variation
Genotype
HEK293 Cells
Humans
Male
Middle Aged
Mutation
Phenotype
Prospective Studies
Switzerland
Young Adult
alpha-Galactosidase
/ genetics
Fabry disease
amenable mutation
lyso-Gb3
migalastat
phenotype
α-Galactosidase activity
Journal
Journal of inherited metabolic disease
ISSN: 1573-2665
Titre abrégé: J Inherit Metab Dis
Pays: United States
ID NLM: 7910918
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
25
04
2019
revised:
12
07
2019
accepted:
19
08
2019
pubmed:
27
8
2019
medline:
3
7
2021
entrez:
27
8
2019
Statut:
ppublish
Résumé
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.
Substances chimiques
1-Deoxynojirimycin
19130-96-2
migalastat
C4XNY919FW
alpha-Galactosidase
EC 3.2.1.22
Types de publication
Journal Article
Multicenter Study
Langues
eng
Sous-ensembles de citation
IM
Pagination
326-333Informations de copyright
© 2019 SSIEM.
Références
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