title: Upregulation of inward rectifying currents and Fabry disease neuropathy.
abstract: Peripheral neuropathy and neuropathic pain are common clinical manifestations of Fabry disease (FD). Although the mechanisms underlying the development of sensory neuropathy remain to be fully elucidated, a chronic ischemic process was proposed. Consequently, this study utilized axonal excitability techniques to gain further insights into the pathophysiological mechanisms underlying the development of FD neuropathy. Median motor and sensory axonal excitability studies were undertaken in 13 FD patients and results were compared to 19 healthy subjects. A "fanning-in" of threshold electrotonus, suggestive of membrane depolarization, was evident only in motor axons in FD patients. In contrast, the sensory axons exhibited a lower threshold in FD (p < 0.05) and a significantly increased hyperpolarizing current/threshold (I/V) gradient (FD 0.48 ± 0.03; controls, 0.31 ± 0.02, p < 0.001), which correlated with clinical scores of disease severity (Rho = 0.65, p < 0.05), neuropathy (Rho = 0.54, p < 0.05) and neuropathic pain (Rho = 0.56, p < 0.05). These findings indicate that upregulation of I(h) , rather than ischemia, may underlie the sensory symptoms and possibly development of neuropathy in FD. Modulation of sensory I(h) may prove therapeutically useful in Fabry disease.
authors.affiliation: Department of Neurology, Sydney Medical School Westmead, University of Sydney, Sydney, Australia.
authors.forename: Nimeshan
authors.initials: N
authors.lastname: Geevasinga
authors.forename: Michel
authors.initials: M
authors.lastname: Tchan
authors.forename: David
authors.initials: D
authors.lastname: Sillence
authors.forename: Steve
authors.initials: S
authors.lastname: Vucic
mesh_terms: D000328:Adult; D001369:Axons / Q000502:physiology; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000502:physiology; D004558:Electric Stimulation; D004568:Electrodiagnosis; D000795:Fabry Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D008297:Male; D008475:Median Nerve / Q000503:physiopathology; D008875:Middle Aged; D009046:Motor Neurons / Q000502:physiology; D053580:Muscle Strength; D009437:Neuralgia / Q000209:etiology; D010147:Pain Measurement; D010525:Peripheral Nerves / Q000378:metabolism / Q000503:physiopathology; D015221:Potassium Channels / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying