830 Fabry rat skin findings demonstrate potential roles of inflammation and lipoatrophy in Fabry disease

Abstract

Fabry disease is an X-linked lysosomal disease caused by α-galactosidase A deficiency. Patients experience distal extremity pain and often develop renal failure, cardiomyopathy, and stroke. Dermatological manifestations include sweating abnormalities and angiokeratomas. To gain a better understanding of disease mechanisms, we generated a Fabry rat model using CRISPR/Cas9 technology and confirmed the absence of α-galactosidase A activity in tissues. Wild type (WT) and Fabry rats were indistinguishable at young ages (weaning-6 months), but aging (9 months+) Fabry rats developed an unkempt appearance, alopecia, and xeroderma. At necropsy, increased effort was required to section the aged Fabry rat skin. These reasons prompted us to histologically examine the skin of 3 Fabry and 3 WT 90-week-old males. The dermal connective tissue layer was thickened and denser in Fabry rat skin, and a prominent band of histiocytes was observed. CD68 staining confirmed the abundance of macrophages in Fabry, but not WT, dermis. Lipoatrophy was apparent in Fabry rat skin, a finding consistent with Fabry males weighing less than WT males. Dilated sebaceous ducts were also noted, suggesting occlusion and thus providing a xeroderma explanation. Fabry rats frequently developed lesions characterized as circular to oval alopecic plaques with erosions and hemorrhagic crusting. The lesions had a predilection for the dorsal head and back and were more commonly seen in Fabry female rats than males. On the microscopic level, the lesions were observed to demonstrate focal ulceration, epidermal spongiosis with microvesiculation, and overlying serum crust. In the dermis, there was a mixed cellular infiltrate, consisting of histiocytes, lymphocytes, and abundant eosinophils. Importantly, no vascular pathology was observed in the lesions. Although angiokeratomas were not observed in Fabry rats, the skin findings indicate that inflammation and lipoatrophy may be prominent mediators of Fabry disease phenotypes in humans.