Rats deficient in \u03b1-galactosidase A develop ocular manifestations of Fabry disease

James J Miller,Christopher A Reid,Kazuhiro Aoki,Iris S Kassem,Nancy M Dahms,Michael Tiemeyer

doi:10.1038/s41598-019-45837-1

James J Miller, Christopher A Reid + Show 4 more

Open Access

https://doi.org/10.1038/s41598-019-45837-1

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Abstract

Fabry disease is an X-linked lysosomal storage disease caused by deficiency of α-galactosidase A. Ocular findings, such as cornea verticillata, cataracts, and retinal vascular tortuosity, serve as important diagnostic markers. We aimed to evaluate ocular phenotypes in α-galactosidase A-deficient (Fabry) rats and hypothesized that these rats would manifest ocular signs similar to those observed in patients. Slit lamp biomicroscopy was used to evaluate the cornea and lens, and retinal vasculature was examined by fluorescein angiography in WT and Fabry rats. Mass spectrometry was used to characterize and quantify ocular glycosphingolipids, and histology and electron microscopy revealed the location of the glycosphingolipid storage. We found that Fabry rats developed corneal and lenticular opacities to a statistically greater degree than WT rats. Retinal vascular morphology did not appear grossly different, but there was vascular leakage in at least one Fabry rat. Fabry rat eyes accumulated substrates of α-galactosidase A, and these α-galactosyl glycoconjugates were found in corneal keratocytes, lens fibers, and retinal vascular endothelial cells. Electron-dense lamellar inclusions were observed in keratocytes. Because Fabry rats recapitulate many ocular phenotypes observed in patients, they can be used to study disease pathogenesis and determine whether ocular findings serve as noninvasive indicators of therapeutic efficacy.

Highlights

One FDA-approved treatment for Fabry disease is enzyme replacement therapy (ERT) where recombinant α-Gal A protein is infused biweekly
Not the typical whorl-like opacities characteristic of cornea verticillata, our slit lamp imaging studies reveal that Fabry rats develop corneal opacities in a characteristic pattern that can be scored, which is reflective of opacity severity
Because enzyme replacement therapy and chaperone therapy are currently available and novel treatments are on the horizon, it is imperative that patients are diagnosed and treated as early as possible to prevent irreversible organ damage

Summary

Introduction

One FDA-approved treatment for Fabry disease is enzyme replacement therapy (ERT) where recombinant α-Gal A protein is infused biweekly. Α-Gal A knockout (KO) mouse models have been important in evaluating therapies to diminish glycosphingolipid storage[13,14], but the utility of the Fabry mouse in studying eye pathology is limited by the fact that ocular phenotypes are not robustly documented in Fabry mice. While there was no overt evidence of retinal tortuosity, Fabry rat eyes accumulate α-galactosyl glycosphingolipids in keratocytes, lens fibers, and retinal vascular endothelial cells. To our knowledge, this is the first study that extensively characterizes ocular phenotypes in an animal model of Fabry disease. Because Fabry rats develop multiple ocular phenotypes similar to those observed in patients, they can be used to better investigate mechanistic pathways of the ocular pathology and the effects of existing and new therapies

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