Diagnosis and Predictive Value of the Ocular Manifestations of Fabry Disease

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PROJECT SUMMARY Lysosomal storage diseases are systemic metabolic disorders caused by pathologic accumulation of byproducts in various cells and organs, including the eye. Fabry disease is the most common lysosomal storage disease and results from a mutation of the X-linked GLA gene causing a deficiency of the enzyme α-galactosidase A (α-Gal A). Glycosphingolipids progressively accumulate, resulting in a shorter and poorer quality of life from renal failure, cardiac dysfunction, cerebrovascular disease, gastrointestinal symptoms, and chronic pain. Patients also have pathognomonic cornea verticillata that is usually present at the time of diagnosis. Other symptoms include cataract, conjunctival and retinal tortuosity, and aneurysmal dilation. Importantly, a direct correlation exists between the prevalence of certain ocular findings and disease severity in Fabry disease with cornea verticillata often leading to the initial diagnosis. The timing of the ocular findings relative to other organ system disease is not well described and difficult to study in humans because of heterogeneity in the patient population. Mouse models have been used in the development of enzyme replacement therapy (ERT), but are limited by the fact that they do not recapitulate ocular phenotypes. Using a Dark Agouti α-Gal A knockout animal model with the corneal, lenticular, and retinal vascular changes seen in patients, we seek to evaluate both knockout rats and humans for an ocular pain and retinal phenotypes not previously evaluated in a in a cohort for this rare disease. Our unique approach integrates the complementary strengths of an animal model, giving the opportunity to study a large controlled population, while human studies determine the clinical significance of pathology. We propose to do this with the following specific aims: 1) evaluate the extent and time course of ocular pathology in a α-Gal A KO rat model of Fabry disease and the effect of early versus later ERT and 2) evaluate human subjects with Fabry Disease for ocular pain and subclinical ocular changes that precede clinically significant disease observed in α-Gal A KO rats. This work is expected to have a significant impact on our understanding lysosomal storage diseases by using an animal model that recapitulates eye symptoms to elucidate the time course of ocular pathology of Fabry disease in relation to systemic symptoms. These findings will aid in the determination of optimal timing of ERT initiation and the efficacy of new therapies, while providing mechanistic insight into the ocular pathology of other lysosomal or metabolic diseases.