Abstract
Fabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of glycolipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fib...
Highlights
Small fiber neuropathy (SFN) is a hallmark of Fabry disease (FD), and neuropathic pain is one of the first symptoms in most patients.[1,2] Pain is experienced by 60% to 80% of boys and girls[3,4] with SFN
One hypothesis is that Gl3 deposits in dorsal root ganglion (DRG) neurons may conclude in neuronal damage with a dying back neuropathy in terms of a ganglionopathy and may result in reduced intraepidermal nerve fiber density (IENFD).[30]
Lower leg IENFD was reduced to 46% in patients compared to controls and to 12.5% in men with impaired renal function
Summary
Small fiber neuropathy (SFN) is a hallmark of Fabry disease (FD), and neuropathic pain is one of the first symptoms in most patients.[1,2] Pain is experienced by 60% to 80% of boys and girls[3,4] with SFN. One hypothesis is that Gl3 deposits in dorsal root ganglion (DRG) neurons may conclude in neuronal damage with a dying back neuropathy in terms of a ganglionopathy and may result in reduced intraepidermal nerve fiber density (IENFD).[30] At the same time, Gl3 deposition in DRG may interfere with the function of cellular membrane proteins, such as ion channels, altering cellular excitability and leading to cytotoxicity resulting in nerve fiber dysfunction and damage This hypothesis fits well with the observed general reduction in intraepidermal nerve fibers in patients with FD found in the skin at the back, which is normally preserved from intraepidermal fiber loss in length-dependent peripheral neuropathies.[31,32] A second hypothesis concerns chronic nerve ischemia secondary to Gl3 deposition within the endothelial cells of the blood vessels supplying nerve fibers.[28] Lyso-Gl3 has been shown to promote SMC proliferation in vitro and has been proposed to play a role in the development of vascular pathology in FD.[33] Another possible hypothesis is that the increase in the number of small regenerating unmyelinated fibers as seen in some cases[34] in spite of the pattern of nerve fiber depletion generates hyperexcitability and spontaneous firing of sprouting unmyelinated neurites arising from nociceptive axons. The relation of SFN, age, and pain in FD has been unclear so far
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