Ocular signs correlate well with disease severity and genotype in Fabry disease.

Susanne Pitz,Laila Arash,Andreas Gal,Andrea Sodi,Sylvain Larroque,Gisela Kalkum,Michael Beck,Nesrin Karabul,Andreas Ohlmann

doi:10.1371/journal.pone.0120814

Abstract

Ocular signs in Fabry disease have generally been regarded to be primarily of diagnostic value. We explored whether ocular findings, alone or in particular in combination with the α-galactosidase A gene mutation, have predictive value for disease severity. Data from the Fabry Outcome Survey (FOS), a large, global database sponsored by Shire, were selected for adult patients who had undergone ophthalmological examination. Three ocular signs were assessed: cornea verticillata, tortuous conjunctival and/or retinal vessels, and cataract. Fabry disease severity was measured using FOS Mainz Severity Score Index and modifications thereof. Ophthalmological data were available for 1203 (699 female, 504 male) adult patients with eye findings characteristic of Fabry disease in 55.1%. Cornea verticillata had a similar distribution in women (51.1%) and men (50.8%), whereas tortuous vessels and Fabry cataract were somewhat more frequent in men than in women. Patients with cornea verticillata, selected as the principal ocular sign for this study, had more severe disease (median score, 20.0) versus those without ocular signs (11.0; P<0.001). This finding could be confirmed by applying age adjusted severity scores. Moreover, the prevalence of cornea verticillata was significantly higher in patients with null (male, 76.9%; female, 64.5%) and missense (male, 79.2%; female, 67.4%) mutations versus mild missense (male, 17.1%; female, 23.1%) and the p.N215S (male, 15.0%; female, 15.6%) mutations (P<0.01). Our analyses show a correlation between the prevalence of ocular changes in Fabry disease and disease severity. Consequently, information on ocular findings and α-galactosidase A gene mutation may help assess the risk for more severe Fabry disease. These observed findings are of notable clinical importance, as Fabry disease is characterized by high clinical course variability and only weak genotype-phenotype correlation at the individual patient level. Further confirmatory studies are needed.

Highlights

Fabry disease is an X-chromosomal lysosomal storage disorder resulting from deficient activity of the enzyme α-galactosidase A
Our analysis suggests that the course of Fabry disease among patients exhibiting eye signs is significantly more severe than among those without ocular findings
As the Fabry Outcome Survey (FOS)-Mainz Severity Score Index (MSSI) in its original description is not corrected for patient age, methods incorporating adjustment for age are mandatory for correct interpretation of pooled data as in a database like the FOS

Summary

Introduction

Fabry disease is an X-chromosomal lysosomal storage disorder resulting from deficient activity of the enzyme α-galactosidase A. Ocular involvement in Fabry disease is characterized by corneal and lens opacities as well as vascular abnormalities [5,6,7,8]. Cornea verticillata manifests as almost pathognomonic corneal deposits. These whorl-like, linear opacities in the inferior part of the cornea have been shown histologically to be located in the epithelium and adjacent anterior stroma [8]. Cornea verticillata does not affect vision, but is the most common ocular sign in Fabry disease; the reported prevalence varies between 44% and 94% among various subpopulations [5,9,10]. Ocular signs have been reported to occur as early as the first decade of life [5]; cornea verticillata has even been described in a 22-week foetus [11]

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Conclusion