Changes in Ionic Conductance Signature of Nociceptive Neurons Underlying Fabry Disease Phenotype

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.

Neuropathic pain in a Fabry disease rat model

“…Previous patch clamp studies with DRG neurons from Fabry mice have focused on changes in voltage-gated sodium, potassium, and calcium channels, but not on mechanical sensitivity or mechanotransduction ion channels (63,64). This is despite the fact that mechanical allodynia is a prevalent symptom in patients with Fabry disease (24).…”

Non-coding RNAs in neuropathic pain

“…miR-18, miR-19a, miR-19b as well as mir-92 are also up-regulated in neuropathic pain models and in turn down-regulate potassium channels including Kcna1, Kcna4, Kcnc4, Kcnd3 and Kcnq5 [73]. The suppression of potassium channels in general increases neuronal excitability and this may be a relevant mechanism causing nociceptor excitation and sensitization [125,126]. In line with the alterations towards hyperexcitability, several down-regulated miRNAs targeting voltage-gated sodium channels may further promote neuronal excitability by releasing the breaks on sodium channel expression: two alpha subunits of voltage-gated sodium channels, Scn3a giving rise to Na v 1.3 and Scn9a giving rise to pain-related Na v 1.7, are targeted by the down-regulated miRNAs miR-30b, miR-96 and miR-183, which probably contributes to up-regulation of the ion channel alpha subunits in neuropathic pain models [94,95,98,105].…”

Role of Gangliosides in Peripheral Pain Mechanisms

“…Symptoms of autonomic neuropathy such as reduced sweating and hypohydrosis, reduced heart rate variability, orthostatic hypotonia and gastrointestinal dysmobility are also frequent complications of the disease [26]. In different animal models, similar abnormalities of sensory and autonomic functions have been observed after genetic deletion of the α-galactosidase gene [28][29][30]. Prominent morphological changes of the affected thin myelinated and unmyelinated sensory axons are the reduction of the intraepidermal fiber density in the skin [31][32][33] and reduction in the density and length of corneal nerve fibers [32,34].…”