Abstract: SA-PO612
Pharmacologic Chaperone Responsiveness in Canadian Patients with Fabry Disease
Session Information
- Noncystic Mendelian Diseases
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Genetic Diseases of the Kidney
- 802 Non-Cystic Mendelian Diseases
Authors
- West, Michael L., Dalhousie University, Halifax, Nova Scotia, Canada
- Bichet, Daniel G., University of Montreal, Montreal, Quebec, Canada
- Sirrs, Sandra, Vancouver General Hospital, Vancouver, Alberta, Canada
Group or Team Name
- Canadian Fabry Disease Initiative Research Group
Background
Fabry disease (FD) is an X-linked lysosomal storage disease due to deficiency of the enzyme α-galactosidase. This results in premature death from renal failure, hypertrophic cardiomyopathy and strokes. Treatment with intravenous enzyme replacement therapy (ERT) is expensive and not curative. Pharmacologic chaperone therapy (PCT) with Migalastat, an oral iminosugar, increases residual enzyme activity by stabilizing the molecule and delivering more enzyme to the lysosome. Recent data suggests that some patients on ERT may derive additional benefit from PCT. We report the prevalence of chaperone responsiveness in Canadian Fabry disease patients as a guide to planning future therapy.
Methods
The Canadian Fabry Disease Initiative (CFDI) is a registry of 466 FD patients followed for up to 10 years. All known GLA gene mutations in CFDI patients were evaluated using a published library of chaperone responsive mutations based on a good laboratory practice-validated HEK cell assay (Benjamin et al Genetics in Medicine 2017;19:430-8).
Results
The majority of Canadian patients with FD are enrolled in the CFDI with ascertainment of 92%. Over 95% have been genotyped. We evaluated 404 FD patients with 143 males, 261 females, mean age 45.0±17.8 (sd), range 8-86 years. ERT use under Canadian Fabry Treatment Guidelines was 50%. Chaperone responsiveness mutations (n=23) were noted in 86 patients (21.3%); missense 95.6%; half were receiving ERT. Non-responsive mutations (n=67) were found in 318 patients (78.7%); missense 53%, deletion/insertion 26%, stop codon 13%, duplication 3%, intronic 3%, frame shift 2%. Patients with chaperone responsive mutations had classic FD phenotype in 72.1%, vs. variant (24.4%) or indeterminate (3.5%) phenotypes. Chaperone responsive mutations varied by region with a maximum prevalence of 48.1% in Alberta (n=25) vs. a low of 2.2% in Nova Scotia (n=2). This is explained in part by the presence of a large Nova Scotia kindred with a chaperone non-responsive A143P mutation.
Conclusion
Oral PCT could be currently used in about one fifth of the Canadian FD population. Only half of those patients meet the current Canadian FD treatment guidelines for ERT suggesting that introduction of chaperone therapy would potentially only offer a change of treatment in a maximum of 40 (10%) FD patients in Canada. These data will help plan future therapy.
Funding
- Commercial Support – Amicus, Shire