Publication Date
2024
Document Type
Dissertation
Committee Members
Mark M. Rich, M.D., Ph.D. (Advisor); Andrew R. Ednie, Ph.D. (Committee Member); Andrew W. Froehle, Ph.D. (Committee Member); Brent D. Foy, Ph.D. (Committee Member); Clintoria Williams, Ph.D. (Committee Member)
Degree Name
Doctor of Philosophy (PhD)
Abstract
Hyperkalemic Periodic Paralysis (hyperKPP) is an inherited channelopathy that leads to incapacitating episodes marked by severe skeletal muscle weakness or total paralysis, often accompanied by muscular stiffness (myotonia). The periods of muscle dysfunction are thought to be caused by the elevation in extracellular potassium (K). This autosomal dominant disorder is associated with mutations in the skeletal muscle voltage-gated sodium channel (Nav1.4). A multitude of inciting factors have been documented, including rest post-exertion, a potassium-rich diet, exposure to cold temperatures, psychological stressors, and fatigue. Given the variability of the triggers and the debilitating manifestation of symptoms, individuals afflicted by hyperKPP have limitations in their daily lives. It was discovered in the early 1990s that gain-of-function mutations in Nav1.4 causing a noninactivating (persistent Na current or NaP) and a left shift of sodium (Na) activation curve cause hyperKPP. The discovery has yielded no novel therapy. The precise mechanisms underlying the symptoms of myotonia and weakness in hyperKPP are not fully understood. Using advanced ex-vivo techniques, novel mechanisms that underlie both myotonia and weakness in hyperKPP were discovered. Currently it is thought that myotonia in hyperKPP is explained by involuntary firing of muscle action potentials (myotonic discharges). A second mechanism was discovered: prolonged contraction triggered by elevation of intracellular calcium (Ca) in electrically silent muscle. The elevation of Ca is not triggered by depolarization of the membrane potential but may instead be initiated by Na overload secondary to persistent activation of NaP. Furthermore, the source of the pathological rise in intracellular Ca is the sarcoplasmic reticulum. The overall myotonia in this disease is mainly attributed to this second mechanism and can be prevented with dantrolene, a ryanodine receptor inhibitor used to treat malignant hyperthermia. Paralysis in hyperKPP is currently thought to be caused by depolarization of the membrane potential due to persistent activation of NaP. It was determined that weakness is not present when muscle is directly stimulated but is severe with nerve stimulation. This finding is inconsistent with loss of muscle excitability as the mechanism underlying weakness. Through intracellular recording of action potentials, it was confirmed that depolarization of the membrane potential is not sufficient in hyperKPP to trigger inexcitability secondary to inactivation of Na channels. Instead, weakness occurs despite the ability of hyperKPP muscle fibers to generate and conduct action potentials. To examine whether failure of neuromuscular transmission at the neuromuscular junction contributes to weakness hyperKPP muscle was treated with an inhibitor of acetylcholinesterase. Inhibition of acetylcholinesterase is a standard treatment for failure of neuromuscular transmission. Treatment both prevented and reversed weakness. Despite being due to gain of function mutations in Na channel, it has been reported that Na channel blockers are ineffective as therapy. The reexamination of this belief found the Na channel blockers mexiletine and ranolazine are very effective in treating both myotonia and weakness. It was also discovered that the Ca channel blocker verapamil is effective, suggesting a potential contribution of Ca entry through Cav1.1 channels to both myotonia and weakness. This study significantly advances our understanding of the underlying mechanisms causing myotonia and weakness in hyperKPP and proposes innovative therapeutic avenues for addressing these debilitating symptoms.
Page Count
176
Department or Program
Biomedical Sciences
Year Degree Awarded
2024
Copyright
Copyright 2024, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
