{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T18:00:40Z","timestamp":1778695240874,"version":"3.51.4"},"reference-count":98,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ICBAS\/BIAL Foundation","award":["PAD n.\u00ba 70342"],"award-info":[{"award-number":["PAD n.\u00ba 70342"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Contactin-associated protein-like 2 (CASPR2) is a transmembrane protein of the neurexin superfamily, essential for clustering voltage-gated potassium channels, particularly Kv1, at the juxtaparanodal regions of myelinated axons. This precise localisation is essential for maintaining normal axonal excitability and preventing aberrant signal propagation. Autoantibodies targeting CASPR2 have been associated with various neurological syndromes, notably peripheral nerve hyperexcitability (PNH), which presents clinically with neuromyotonia and myokymia. PNH is characterised by distinctive electrophysiological findings, including neuromyotonic discharges, myokymic discharges, and afterdischarges, which provide diagnostic value and insight into underlying pathophysiology. This review explores the mechanisms of anti-CASPR2-associated PNH, focusing on how antibody-mediated disruption of Kv1 channel clustering leads to altered axonal excitability. Current evidence suggests that both the distal and proximal segments of the axon are sites of pathological activity, where impairments in action potential termination and re-entry prevention result in spontaneous, repetitive discharges. While afterdischarges likely originate within the axon, the precise location\u2014whether in the alpha-motoneuron soma or axon\u2014is uncertain. The involvement of spinal inhibitory circuits has also been proposed, though it remains speculative. Understanding the neurophysiological features of anti-CASPR2-associated PNH is essential for improving diagnostic accuracy and guiding treatment strategies. Further research is needed to clarify the mechanisms of CASPR2-related hyperexcitability.<\/jats:p>","DOI":"10.3390\/biom15091262","type":"journal-article","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T08:28:15Z","timestamp":1756715295000},"page":"1262","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Neuromyotonia and CASPR2 Antibodies: Electrophysiological Clues to Disease Pathophysiology"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4212-906X","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Moura","sequence":"first","affiliation":[{"name":"Department of Neurology, Centro Hospitalar Universit\u00e1rio de Santo Ant\u00f3nio, Unidade Local de Sa\u00fade de Santo Ant\u00f3nio, 4099-001 Porto, Portugal"},{"name":"Unit for Multidisciplinary Research in Biomedicine (UMIB), School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal"},{"name":"ITR\u2014Laboratory for Integrative and Translational Research in Population Health, Rua das Taipas 135, 4050-600 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pietro","family":"Antenucci","sequence":"additional","affiliation":[{"name":"Unit of Clinical Neurology, Neurosciences and Rehabilitation Department, University of Ferrara, Via Aldo Moro 8, Cona, 44121 Ferrara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ester","family":"Coutinho","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal"},{"name":"Centre for Innovative Biomedicine and Biotechnology (CiBB), University of Coimbra, Rua Larga, 3004-504 Coimbra, Portugal"},{"name":"Cat\u00f3lica Medical School, Universidade Cat\u00f3lica Portuguesa, Estr. Oct\u00e1vio Pato, 2635-631 Rio de Mouro, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8185-286X","authenticated-orcid":false,"given":"Kailash P.","family":"Bhatia","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, 33 Queen Square, London WC1N 3BG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorenzo","family":"Rocchi","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences and Public Health, University of Cagliari, 09124 Cagliari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7103-5209","authenticated-orcid":false,"given":"Anna","family":"Latorre","sequence":"additional","affiliation":[{"name":"Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, 33 Queen Square, London WC1N 3BG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1152\/physrev.00010.2016","article-title":"Autoantibodies to Synaptic Receptors and Neuronal Cell Surface Proteins in Autoimmune Diseases of the Central Nervous System","volume":"97","author":"Dalmau","year":"2017","journal-title":"Physiol. 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