Abstract
The first symptom arising in many Fabry patients is neuropathic pain due to changes in small myelinated and unmyelinated fibers in the periphery, which is subsequently followed by a loss of sensory perception. Here we studied changes in the peripheral nervous system of Fabry patients and a Fabry mouse model induced by deletion of α-galactosidase A (Gla−/0). The skin innervation of Gla−/0 mice resembles that of the human Fabry patients. In Fabry diseased humans and Gla−/0 mice, we observed similar sensory abnormalities, which were also observed in nerve fiber recordings in both patients and mice. Electrophysiological recordings of cultured Gla−/0 nociceptors revealed that the conductance of voltage-gated Na+ and Ca2+ currents was decreased in Gla−/0 nociceptors, whereas the activation of voltage-gated K+ currents was at more depolarized potentials. Conclusively, we have observed that reduced sensory perception due to small-fiber degeneration coincides with altered electrophysiological properties of sensory neurons.
Highlights
Fabry disease is a rare, life-limiting X-linked monogenetic multi-organ disorder caused by deficiency or loss of α-galactosidase A (α-Gal A) [1]
Fabry disease patients regularly suffer from small-fiber neuropathy which is associated with neuropathic pain and severe loss of intraepidermal innervation, in particular the thinly myelinated Aδ and unmyelinated C-fibers [6]
To explore to which extent the Gla−/0 mice, lacking functional α-Gal A, share similarities with Fabry disease patients, the innervation of hindpaw glabrous skin of adult Gla−/0 and Wt mice was examined by indirect immune fluorescence microscopy
Summary
Fabry disease is a rare, life-limiting X-linked monogenetic multi-organ disorder caused by deficiency or loss of α-galactosidase A (α-Gal A) [1]. A transgenic mouse, which lacks functional α-Gal A enzyme, is available and serves as a model for the human Fabry disease [2]. Symptoms of human Fabry disease include severe pain episodes starting in childhood, followed by autonomic and sensory impairment, which reflects damage to small fibers of the peripheral and autonomic nervous systems, kidney failure, and cardiological as well as other symptoms [3,4,5,6,7,8]. In line with human findings, transgenic mice modeling the disease show lipid inclusions in heart and kidney and the nervous system [2] and like in patients, these alterations aggravate with increasing age [10, 11]. The causal treatment, enzyme replacement therapy that has become available since 2001, is only partially effective
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have