{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T06:55:22Z","timestamp":1790924122617,"version":"4.1.0"},"reference-count":9,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Pathogenic variants in ATP1A3 are classically associated with alternating hemiplegia of childhood, CAPOS syndrome, and rapid\u2010onset dystonia\u2010parkinsonism. However, the phenotypic spectrum of ATP1A3\u2010related disease has expanded considerably in recent years, including atypical presentations with spasticity and hereditary spastic paraplegia\u2010like phenotypes. We describe a 43\u2010year\u2010old woman who developed a progressive upper motor neuron syndrome characterized by spastic paraparesis, generalized hyperreflexia, bilateral Babinski signs, inexhaustible ankle clonus, spastic dysarthria, dysphagia, and mild cerebellar involvement. Extensive metabolic, autoimmune, infectious, neurophysiological, neuroimaging, and genetic investigations failed to identify an alternative diagnosis. Targeted next\u2010generation sequencing identified a heterozygous ATP1A3 NM_152296.4:c.2984G&gt;A, p.(Arg995His). Familial segregation analysis demonstrated a confirmed de novo occurrence with biological parentage verification. The variant affects a highly conserved residue within the transmembrane M8 domain, is absent from population databases, and is predicted to be deleterious by multiple in silico tools. According to ACMG\/AMP criteria, the variant fulfilled PM2 and PP3 and is currently classified as a variant of uncertain significance (VUS). This case suggests a possible expansion of the phenotypic spectrum of ATP1A3\u2010related disease and represents, to our knowledge, the first reported adult\u2010onset primary lateral sclerosis\u2010like phenotype associated with an ATP1A3 variant. These findings suggest that ATP1A3 should be considered in the genetic evaluation of unexplained adult\u2010onset upper motor neuron syndromes.<\/jats:p>","DOI":"10.1111\/cge.70254","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T06:39:36Z","timestamp":1790923176000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A De Novo\n                    <scp>ATP1A3<\/scp>\n                    p.\n                    <scp>Arg995His<\/scp>\n                    Variant in a Patient With an Adult\u2010Onset Primary Lateral Sclerosis\u2010Like Syndrome"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3319-583X","authenticated-orcid":false,"given":"Pablo","family":"Hernandez\u2010Vitorique","sequence":"first","affiliation":[{"name":"Department of Neurology Hospital Universitario Virgen de la Victoria  M\u00e1laga Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de M\u00e1laga (IBIMA\u2010Plataforma BIONAND)  M\u00e1laga Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6732-9631","authenticated-orcid":false,"given":"Marta","family":"Garc\u00eda de Burgos","sequence":"additional","affiliation":[{"name":"Clinical Genetics Unit, Clinical Laboratory Department Hospital Regional Universitario de M\u00e1laga  M\u00e1laga Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Campos Villegas","sequence":"additional","affiliation":[{"name":"Department of Neurology Hospital Universitario Virgen de la Victoria  M\u00e1laga Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Jos\u00e9","family":"G\u00f3mez Heredia","sequence":"additional","affiliation":[{"name":"Department of Neurology Hospital Universitario Virgen de la Victoria  M\u00e1laga Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pilar","family":"Carbonell Corvillo","sequence":"additional","affiliation":[{"name":"Department of Neurology Hospital Universitario Virgen de la Victoria  M\u00e1laga Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2022.924788"},{"key":"e_1_2_9_3_1","first-page":"1993","volume-title":"GeneReviews [Internet]","author":"Brashear A.","year":"2024"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000200927"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.637890"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.17712\/nsj.2023.3.20220131"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/JNNP\u20102019\u2010322541"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awad124"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bdcasr.2024.100016"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/GIM.2015.30"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70254","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cge.70254","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70254","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T06:39:37Z","timestamp":1790923177000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.70254"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,1]]},"references-count":9,"alternative-id":["10.1111\/cge.70254"],"URL":"https:\/\/doi.org\/10.1111\/cge.70254","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,1]]},"assertion":[{"value":"2026-07-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"cge.70254"}}