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Genetic studies were performed with targeted sequencing of all known myopathy genes. Functional changes resulting from these variants were studied with HEK293T cells, by using a whole\u2010cell patch clamp.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Five <jats:italic>SCN4A<\/jats:italic> variants were identified: c.662 T &gt; C p.(F221S), c.2143G &gt; A p.(A715T), c.4352G &gt; A p.(R1451H), c.3610 A &gt; G p.(N1204D), and c.4255 T &gt; C, p.(F1419L). Patients had exercise\u2010 and\/or cold\u2010induced myalgia, muscle stiffness or cramping, and varying degrees of muscle weakness. On examination, some but not all patients had percussion myotonia or findings compatible with paramyotonia. One patient with the A715T variant also had eyelid myotonia. The patient with the F221S variant had ptosis, weakness in hip flexion, and mild muscle hypertrophy in the calves. EMG showed myotonic discharges in all the patients examined except for the patient with N1204D. Electrophysiological exercise tests demonstrated results compatible with the Fournier pattern in six patients. All but the N1204D variant showed gain\u2010of\u2010function features upon functional expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The clinical and genetic findings suggested that all five variants were pathogenic, whereas functional data did not confirm association with myotonia for N1204D. Our results expand the mutational spectrum of the <jats:italic>SCN4A<\/jats:italic> gene. The reported variants should be considered in patients with paramyotonia, or in patients with exercise\u2010induced myalgia or muscle cramping and who demonstrate myotonia in EMG.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ene.70157","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T12:01:17Z","timestamp":1748347277000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Novel <scp>SCN4A<\/scp> Variants Associated With Myalgic Myotonic Disorder or Paramyotonia"],"prefix":"10.1111","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0426-0259","authenticated-orcid":false,"given":"Vesa","family":"Periviita","sequence":"first","affiliation":[{"name":"Department of Neurology Tampere University Hospital  Tampere Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roope","family":"M\u00e4nnikk\u00f6","sequence":"additional","affiliation":[{"name":"UCL Queen 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