Ion channels and pain in Fabry disease

Abstract

Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A (α-Gal A) activity which results in progressive accumulation of globotriaosylceramide (Gb3) and related metabolites. One prominent feature of Fabry disease is neuropathic pain. Accumulation of Gb3 has been documented in dorsal root ganglia (DRG) as well as other neurons, and has lately been associated with the mechanism of pain though the pathophysiology is still unclear. Small fiber (SF) neuropathy in FD differs from other entities in several aspects related to the perception of pain, alteration of fibers as well as drug therapies used in the practice with patients, with therapies far from satisfying. In order to develop better treatments, more information on the underlying mechanisms of pain is needed. Research in neuropathy has gained momentum from the development of preclinical models where different aspects of pain can be modelled and further analyzed. This review aims at describing the different in vitro and FD animal models that have been used so far, as well as some of the insights gained from their use. We focus especially in recent findings associated with ion channel alterations -that apart from the vascular alterations-, could provide targets for improved therapies in pain.

The Heart in Fabry Disease: Mechanisms Beyond Storage and Forthcoming Therapies

“…Birket and colleagues [41] demonstrated enhanced function of sodium and calcium channels, resulting in higher and shorter spontaneous action potentials, in FD cardiomyocytes obtained from induced pluripotent stem cells. These findings are in line with similar results on neuronal ion channels, thus suggesting that stored glycosphingolipids may alter ion channel expression and/or cell membrane trafficking, interfering with the electrical properties of cardiomyocytes [42]. Indeed, Namdar and colleagues [43] hypothesized that an increased conduction velocity in atrial and ventricular myocardium may underlie the electrocardiographic abnormalities in FD, including the presence of a short PR interval in the absence of an accessory pathway.…”

Neurological Manifestations of Fabry Disease: Literature Review

“…Pain is one of the earliest symptoms of FD, the onset of the pain syndrome most often occurs at the age of 3 to 16 years, but pain can also appear before the age of 1 year and in older people [7]. According to data from the FD registry of 1,765, neuropathic pain was present in 62% of men and 41% of women, with an average age of onset of 9 and 10 years, respectively [9], [10].…”

Fabry disease: Mechanism and therapeutics strategies

“…GLA deficiency in patients with Fabry disease results in abnormal glycosphingolipid metabolism and the progressive accumulation of Gb3 ( Aerts et al, 2008 ; Kang et al, 2019 ). With disease progression, patients display multiple clinical phenotypes, such as cardiovascular disease, neuropathic pain, and even increased risk of early death ( Frustaci et al, 2014 ; Aguiar et al, 2018 ; Uceyler et al, 2019 ; Weissmann et al, 2021 ). However, the cellular pathogenic cascade underlying how GLA deficiency results in progressive clinical symptoms remains unclear; moreover, the associated pathogenic cascade has already been initiated before the onset of the organ symptoms of Fabry disease, making de novo diagnosis difficult ( Jabbarzadeh-Tabrizi et al, 2020 ; Spinelli et al, 2020 ).…”