ABSTRACT
Patients in rural and underserved areas face significant barriers in accessing specialty care due to unavailability of services, geographic isolation, travel burden, and other cultural and socioeconomic factors.1 Pediatric dermatology is among the top three subspecialties that provides routine care for pediatric patients, however, shortage and maldistribution of pediatric dermatologists have remained a major hurdle for those living in remote and isolated areas.2 Pediatric dermatologists cluster in urban areas with high-patient volume and estimated wait times for new patients that often exceed 13 weeks, making access one of the major drivers of inequity for rural patients.2-4.
Subject(s)
Dermatology , Interdisciplinary Placement , Medicine , Humans , Child , Bacteria , Law EnforcementABSTRACT
Hypokalemic periodic paralysis is a skeletal muscle disease characterized by episodic weakness associated with low serum potassium. We compared clinical and biophysical effects of R222W, the first hNaV1.4 domain I mutation linked to this disease. R222W patients exhibited a higher density of fibers with depolarized resting membrane potentials and produced action potentials that were attenuated compared to controls. Functional characterization of the R222W mutation in heterologous expression included the inactivation deficient IFM/QQQ background to isolate activation. R222W decreased sodium current and slowed activation without affecting probability. Consistent with the phenotype of muscle weakness, R222W shifted fast inactivation to hyperpolarized potentials, promoted more rapid entry, and slowed recovery. R222W increased the extent of slow inactivation and slowed its recovery. A two-compartment skeletal muscle fiber model revealed that defects in fast inactivation sufficiently explain action potential attenuation in patients. Molecular dynamics simulations showed that R222W disrupted electrostatic interactions within the gating pore, supporting the observation that R222W promotes omega current at hyperpolarized potentials. Sodium channel inactivation defects produced by R222W are the primary driver of skeletal muscle fiber action potential attenuation, while hyperpolarization-induced omega current produced by that mutation promotes muscle fiber depolarization.