{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T05:55:17Z","timestamp":1771653317979,"version":"3.50.1"},"reference-count":68,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T00:00:00Z","timestamp":1752451200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["AR074985"],"award-info":[{"award-number":["AR074985"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["AR081675"],"award-info":[{"award-number":["AR081675"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Hyperkalemic periodic paralysis (hyperKPP) is characterized by attacks of transient weakness. A subset of hyperKPP patients suffers from transient involuntary contraction of muscle (myotonia). The goal of this study was to determine mechanisms causing myotonia in hyperKPP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Intracellular electrophysiology, single\u2010fiber Ca<jats:sup>2+<\/jats:sup> imaging, and whole muscle contractility studies were performed in a mouse model of hyperKPP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Myotonia in hyperkPP was caused by both involuntary myogenic action potentials (AP myotonia) lasting less than 5\u2009min and action potential\u2010independent myotonia (non\u2010AP myotonia) lasting over 1\u2009h. Non\u2010AP myotonia was caused by prolonged subthreshold depolarization and elevated intracellular Ca<jats:sup>2+<\/jats:sup> in the absence of action potentials. Treatment with dantrolene effectively mitigated non\u2010AP myotonia, suggesting that the source of Ca<jats:sup>2+<\/jats:sup> was the sarcoplasmic reticulum. Although non\u2010AP myotonia occurred in the absence of action potentials, Na<jats:sup>+<\/jats:sup> channel blockers were effective as therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>We propose myotonia in hyperKPP occurs via two mechanisms: (1) suprathreshold depolarization triggering action potentials that are detectable with EMG and (2) sustained subthreshold depolarization resulting in Na<jats:sup>+<\/jats:sup> overload and Ca<jats:sup>2+<\/jats:sup> leak from the sarcoplasmic reticulum. Notably, clinical diagnostics such as EMG cannot detect the second mechanism as it occurs in the absence of action potentials. Currently, only a minority of patients with hyperKPP are treated with Na<jats:sup>+<\/jats:sup> channel blockers and none are treated with dantrolene. Our data suggest hyperKPP patients, as well as patients with a number of other neuromuscular disorders, may benefit from trials of these therapies, even if they do not have myotonia detectable clinically or by EMG.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.70134","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T11:49:26Z","timestamp":1752493766000},"page":"2056-2067","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Discovery and Treatment of Action Potential\u2010Independent Myotonia in Hyperkalemic Periodic Paralysis"],"prefix":"10.1002","volume":"12","author":[{"given":"Chris","family":"Dupont","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Cell Biology and Physiology Wright State University  Dayton Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam","family":"Deardorff","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Cell Biology and Physiology Wright State University  Dayton Ohio USA"},{"name":"Department of Clinical Neurosciences Wright State University  Dayton Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Murad","family":"Nawaz","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Cell Biology and Physiology Wright State University  Dayton Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew A.","family":"Voss","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences Wright State University  Dayton Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6956-5531","authenticated-orcid":false,"given":"Mark M.","family":"Rich","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Cell Biology and Physiology Wright State University  Dayton Ohio USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7,14]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/354387a0"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(91)90064-7"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(93)90321-H"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(93)90168-Q"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.2040-4603.2015.tb00630.x"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10061521"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.12656"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201611603"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25017"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP286636"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1088\/0967-3334\/36\/7\/N103"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201511476"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00166.2013"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(57)90318-2"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/92.2.345"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/240217a0"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/279391a0"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12354"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.114.302938"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1113\/expphysiol.2005.031435"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1991.71.3.849"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(92)91281-T"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0704307"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.118.4.355"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2012.12607"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000004229"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-013-7025-9"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2022.114303"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.65691"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.91.5.737"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25646"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.054973"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.4161\/chan.5.2.14851"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000233841.75824.0f"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2044.2004.03658.x"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.31.18465"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2011.01.026"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvu262"},{"key":"e_1_2_9_40_1","first-page":"1687","article-title":"Ryanodine Receptor Dysfunction in Human Disorders. Biochim Biophys Acta Mol","volume":"1865","author":"Kushnir A.","year":"2018","journal-title":"Cell Research"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.36.5.682"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.33.12.1615"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.27241"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1990.00530090091018"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000143383.91137.00"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a005579"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-1283"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2023.102778"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.880140603"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.32.8.827"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.880060506"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.26845"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-014-0300-3"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awz410"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000209164"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2016.75"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780380104"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(12)70204-1"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2011.03.013"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.22249"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.24037"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000003846"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2011.05.006"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.24672"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000290831.08585.2c"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.25160"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.berh.2010.01.012"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.05.014"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.4081\/ejtm.2020.8982"}],"container-title":["Annals of Clinical and Translational Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.70134","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T01:20:59Z","timestamp":1760404859000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acn3.70134"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,14]]},"references-count":68,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1002\/acn3.70134"],"URL":"https:\/\/doi.org\/10.1002\/acn3.70134","archive":["Portico"],"relation":{},"ISSN":["2328-9503","2328-9503"],"issn-type":[{"value":"2328-9503","type":"print"},{"value":"2328-9503","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,14]]},"assertion":[{"value":"2025-04-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}