{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T15:40:47Z","timestamp":1782229247068,"version":"3.54.5"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,10,26]],"date-time":"2023-10-26T00:00:00Z","timestamp":1698278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p>Hereditary myopathies represent a clinically and genetically heterogeneous group of neuromuscular disorders, characterized by highly variable clinical presentations and frequently overlapping phenotypes with other neuromuscular disorders, likely influenced by genetic and environmental modifiers. Genetic testing is often challenging due to ambiguous clinical diagnosis. Here, we present the case of a family with clinical and Electromyography (EMG) features resembling a myotonia-like disorder in which Whole Exome Sequencing (WES) analysis revealed the co-segregation of two rare missense variants in <jats:italic>UBR4<\/jats:italic> and <jats:italic>HSPG2<\/jats:italic>, genes previously associated with episodic ataxia 8 (EA8). A review of the literature highlighted a striking overlap between the clinical and the molecular features of our family and the previously described episodic ataxias (EAs), which raises concerns about the genotype\u2013phenotype correlation, clinical variability, and the confounding overlap in these groups of disorders. This emphasizes the importance of thoroughly framing the patient's phenotype. The more clear-cut the diagnosis, the easier the identification of a genetic determinant, and the better the prognosis and the treatment of patients.<\/jats:p>","DOI":"10.3389\/fneur.2023.1224241","type":"journal-article","created":{"date-parts":[[2023,10,27]],"date-time":"2023-10-27T00:00:54Z","timestamp":1698364854000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Case report: Episodic ataxia without ataxia?"],"prefix":"10.3389","volume":"14","author":[{"given":"Andrea","family":"Gaudio","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Gotta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clarissa","family":"Ponti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Sanguineri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Trevisan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Geroldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Patrone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Gemelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corrado","family":"Cabona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guja","family":"Astrea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Fiorillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Gustincich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Grandis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Mandich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,10,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2484","DOI":"10.1093\/brain\/awm126","article-title":"CINCH investigators. Primary episodic ataxias: diagnosis, pathogenesis, and treatment","volume":"130","author":"Jen","year":"2007","journal-title":"Brain."},{"key":"B2","doi-asserted-by":"crossref","DOI":"10.5772\/intechopen.76076","article-title":"\u2018Hereditary Myopathies'","author":"Gonz\u00e1lez","year":"2018","journal-title":"Muscle Cell and Tissue\u2014Current Status of Research Field. InTech"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1768","DOI":"10.1016\/j.clinph.2009.07.003","article-title":"Clinical neurophysiology of the episodic ataxias: insights into ion channel dysfunction in vivo","volume":"120","author":"Tomlinson","year":"2009","journal-title":"Clin Neurophysiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"129","DOI":"10.14802\/jmd.16028","article-title":"Episodic ataxias: clinical and genetic features","volume":"9","author":"Choi","year":"2016","journal-title":"J Mov Disord."},{"key":"B5","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1038\/ejhg.2013.173","article-title":"A novel locus for episodic ataxia: UBR4 the likely candidate","volume":"22","author":"Conroy","year":"2014","journal-title":"Eur J Hum Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1531","DOI":"10.1086\/302909","article-title":"Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia","volume":"66","author":"Escayg","year":"2000","journal-title":"Am J Hum Genet."},{"key":"B7","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1212\/01.WNL.0000172638.58172.5a","article-title":"Mutation in the glutamate transporter EAAT1 causes episodic ataxia, hemiplegia, and seizures","volume":"65","author":"Jen","year":"2005","journal-title":"Neurology."},{"key":"B8","doi-asserted-by":"publisher","first-page":"9","DOI":"10.5334\/tohm.747","article-title":"Episodic ataxias: primary and secondary etiologies, treatment, and classification approaches","volume":"13","author":"Hassan","year":"2023","journal-title":"Tremor Other Hyperkinet Mov (N Y)."},{"key":"B9","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1002\/mus.27448","article-title":"An integrated approach to the evaluation of patients with asymptomatic or minimally symptomatic hyperCKemia","volume":"65","author":"Gemelli","year":"2022","journal-title":"Muscle Nerve"},{"key":"B10","doi-asserted-by":"publisher","first-page":"75","DOI":"10.3390\/biomedicines9010075","article-title":"Musculoskeletal features without ataxia associated with a novel de novo mutation in KCNA1 impairing the voltage sensitivity of Kv1.1 channel","volume":"9","author":"Imbrici","year":"2021","journal-title":"Biomedicines."},{"key":"B11","doi-asserted-by":"publisher","first-page":"6472","DOI":"10.3390\/ijms21186472","article-title":"Episodic ataxias: faux or real?","volume":"21","author":"Giunti","year":"2020","journal-title":"Int J Mol Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1136\/jnnp.2008.163402","article-title":"A wide spectrum of clinical, neurophysiological and neuroradiological abnormalities in a family with a novel CACNA1A mutation","volume":"81","author":"Romaniello","year":"2010","journal-title":"J Neurol Neurosurg Psychiatry."},{"key":"B13","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1212\/WNL.0b013e3181ea9ee3","article-title":"Nongenetic factors influence severity of episodic ataxia type 1 in monozygotic twins","volume":"75","author":"Graves","year":"2010","journal-title":"Neurology."},{"key":"B14","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/j.tins.2010.02.005","article-title":"Human ataxias: a genetic dissection of inositol triphosphate receptor (ITPR1)-dependent signaling","volume":"33","author":"Schorge","year":"2010","journal-title":"Trends Neurosci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"8323","DOI":"10.3390\/ijms22158323","article-title":"Signaling pathways regulated by UBR Box-containing E3 Ligases","volume":"22","author":"Kim","year":"2021","journal-title":"Int J Mol Sci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.1007\/s00018-014-1788-8","article-title":"p600\/UBR4 in the central nervous system","volume":"72","author":"Parsons","year":"2015","journal-title":"Cell Mol Life Sci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e0202260","DOI":"10.1371\/journal.pone.0202260","article-title":"The N-recognin UBR4 of the N-end rule pathway is required for neurogenesis and homeostasis of cell surface proteins","volume":"13","author":"Kim","year":"2018","journal-title":"PLoS One."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1268","DOI":"10.1016\/j.celrep.2019.06.094","article-title":"A key role for the ubiquitin ligase ubr4 in myofiber hypertrophy in drosophila and mice","volume":"28","author":"Hunt","year":"2019","journal-title":"Cell Rep."},{"key":"B19","doi-asserted-by":"publisher","first-page":"632336","DOI":"10.3389\/fneur.2021.632336","article-title":"A novel pathogenic HSPG2 mutation in schwartz-jampel syndrome","volume":"12","author":"Lin","year":"2021","journal-title":"Front Neurol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1093\/glycob\/cwm043","article-title":"Perlecan\u2013a multifunctional extracellular proteoglycan scaffold","volume":"17","author":"Farach-Carson","year":"2007","journal-title":"Glycobiology."},{"key":"B21","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1038\/nn801","article-title":"Absence of acetylcholinesterase at the neuromuscular junctions of perlecan-null mice","volume":"5","author":"Arikawa-Hirasawa","year":"2002","journal-title":"Nat Neurosci."},{"key":"B22","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/S0166-2236(03)00077-8","article-title":"PerleCan fix your muscle AChEs","volume":"26","author":"Steen","year":"2003","journal-title":"Trends Neurosci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"3166","DOI":"10.1093\/hmg\/ddn213","article-title":"Evidence of a dosage effect and a physiological endplate acetylcholinesterase deficiency in the first mouse models mimicking Schwartz-Jampel syndrome neuromyotonia","volume":"17","author":"Stum","year":"2008","journal-title":"Hum Mol Genet."},{"key":"B24","doi-asserted-by":"publisher","first-page":"556","DOI":"10.3390\/genes9110556","article-title":"Modular proteoglycan perlecan\/HSPG2: mutations, phenotypes, and functions","volume":"9","author":"Martinez","year":"2018","journal-title":"Genes (Basel)."},{"key":"B25","doi-asserted-by":"publisher","first-page":"13855","DOI":"10.1038\/s41598-017-14254-7","article-title":"Genetic variants associated with episodic ataxia in Korea","volume":"7","author":"Choi","year":"2017","journal-title":"Sci Rep."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2023.1224241\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,27]],"date-time":"2023-10-27T00:00:57Z","timestamp":1698364857000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2023.1224241\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,26]]},"references-count":25,"alternative-id":["10.3389\/fneur.2023.1224241"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2023.1224241","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,26]]},"article-number":"1224241"}}