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. 2017 Nov;54(11):781-786.
doi: 10.1136/jmedgenet-2017-104826. Epub 2017 Jul 29.

Reduction of podocyte globotriaosylceramide content in adult male patients with Fabry disease with amenable GLA mutations following 6 months of migalastat treatment

Michael Mauer  1 , Alexey Sokolovskiy  2 , Jay A Barth  3 , Jeffrey P Castelli  3 , Hadis N Williams  3 , Elfrida R Benjamin  3 , Behzad Najafian  2
Affiliations

Reduction of podocyte globotriaosylceramide content in adult male patients with Fabry disease with amenable GLA mutations following 6 months of migalastat treatment

Michael Mauer et al. J Med Genet. 2017 Nov.

Abstract

Objective: Deficiency of α-galactosidase A (αGal-A) in Fabry disease leads to the accumulation mainly of globotriaosylceramide (GL3) in multiple renal cell types. Glomerular podocytes are relatively resistant to clearance of GL3 inclusions by enzyme replacement therapy (ERT). Migalastat, an orally bioavailable small molecule capable of chaperoning misfolded αGal-A to lysosomes, is approved in the European Union for the long-term treatment of patients with Fabry disease and amenable GLA (α-galactosidase A enzyme) mutations. We aimed to examine if migalastat reduces GL3 content of podocytes in Fabry disease.

Methods and analysis: We compared paired renal biopsies of eight adult men with amenable Fabry disease mutations at baseline and after 6 months of treatment with 150 mg migalastat every other day using quantitative unbiased electron microscopic morphometric methods.

Results: Migalastat treatment led to a reduction in mean total GL3 inclusion volume per podocyte in renal biopsies from baseline to 6 months. This reduction correlated precisely with reduced mean podocyte volume. There was also a direct relationship between reduction in podocyte foot process width and the reduction in mean total podocyte GL3 content following 6 months of migalastat treatment, suggestive of reduced podocyte injury.

Conclusion: Migalastat treatment of 6 months duration in eight male patients with Fabry disease demonstrated effective GL3 clearance from the podocyte, an important and relatively ERT-resistant glomerular cell.

Keywords: Fabry; GL3; chaperone; globotriaosylceramide; migalastat; podocyte.

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Conflict of interest statement

Competing interests: BN is a recipient of investigator initiated Genzyme research grants, a consultant to Genzyme and has received speaker’s honoraria and travel support from Genzyme. He is also a member of the Medical Advisory Board of Amicus and performs kidney biopsy studies for Amicus. These interests have been reviewed and managed by the University of Washington in accordance to its conflict of interest policies. MM is a member of the Genzyme sponsored North American Fabry Registry Advisory Board, a recipient of investigator initiated Genzyme research grants, a consultant to Genzyme for clinical trial design, and a speaker at Genzyme educational meetings. These interests have been reviewed and managed by the University of Minnesota in accordance to its conflict of interest policies. He is also a consultant to and performs kidney biopsy studies for Amicus and has served as grant reviewer for Shire.

Figures

Figure 1
Figure 1
(A) Two representative glomeruli from a male patient with Fabry disease with amenable mutation at baseline (left) and 6 months (right) after migalastat treatment. Inlays show magnified views of two representative podocytes. The podocyte after 6 months migalastat (right) still contains many GL3 (globotriaosylceramide) inclusions, but is smaller than the podocyte at baseline (left). (B–D) Each line represents one case at baseline (left) and 6 months after migalastat treatment (right). (B) Volume of GL3 inclusions/podocyte (V(Inc/PC)) at baseline and after 6 months of migalastat treatment in patients with Fabry disease. (C) Mean podocyte volume (V(PC)) at baseline and after 6 months of migalastat treatment in patients with Fabry disease. (D) Volume density or volume fraction of GL3 inclusions/podocyte (Vv(Inc/PC)) at baseline and after 6 months of migalastat treatment in patients with Fabry disease.
Figure 2
Figure 2
Foot process width in normal controls (circles on the left side) and at baseline and after 6 months of migalastat treatment in patients with Fabry disease. Each line represents one case at baseline (left) and 6 months after migalastat treatment (right).
Figure 3
Figure 3
(A) Change in the volume of inclusions per podocyte (∆V(Inc/PC)) and change in foot process width at baseline and after 6 months of migalastat treatment in patients with Fabry disease. (B) Change in the mean volume of podocytes (∆V(PC)) and change in foot process width at baseline and after 6 months of migalastat treatment in patients with Fabry disease.
Figure 4
Figure 4
(A) Change in volume fraction of GL3 inclusions/podocyte (∆Vv(Inc/PC)) and change in plasma lyso-Gb3 at baseline and after 6 months of migalastat treatment in patients with Fabry disease. (B) Change in volume of GL3 inclusions/podocyte (∆V(Inc/PC)) and change in plasma lyso-Gb3 at baseline and after 6 months of migalastat treatment in patients with Fabry disease. GL3, globotriaosylceramide.
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