{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T04:06:25Z","timestamp":1777867585922,"version":"3.51.4"},"reference-count":11,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"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":["Intl J of Devlp Neuroscience"],"published-print":{"date-parts":[[2026,4]]},"abstract":"ABSTRACT<\/jats:title>\n \n Variants in\n ATP8A2<\/jats:italic>\n gene have been traditionally associated with cerebellar ataxia, mental retardation and disequilibrium syndrome type 4 (CAMRQ4). However, this nomenclature fails to capture the predominantly extrapyramidal and encephalopathic nature of the most severe presentation of the\n ATP8A2<\/jats:italic>\n \u2010related phenotypic spectrum.\n <\/jats:p>\n We report two siblings with a novel homozygous ATP8A2 frameshift variant (p.Ser839Glyfs*21) presenting with a complex neurodevelopmental encephalopathy. Their phenotype was characterized by very early\u2010onset hyperkinetic movement disorders, including chorea, dystonia and myoclonus, accompanied by optic atrophy and sensorineural hearing loss. A critical literature review suggests that the profound neuromotor impairment in these patients often precludes an accurate assessment of ataxia, while hyperkinetic movements predominate. The multisystem involvement (ophthalmoplegia, ptosis and sensory loss) frequently mimics mitochondrial disorders, further complicating the diagnostic path. We argue that the current OMIM classification is restrictive and clinically misleading.<\/jats:p>\n \n We therefore propose formally revising the clinical definition of\n ATP8A2<\/jats:italic>\n \u2010related disorders to emphasize early\u2010onset complex encephalopathy with movement disorders, rather than ataxia, as the hallmark of severe cases. Integrating ATP8A2 into next\u2010generation sequencing (NGS) panels for early\u2010onset hyperkinesia is essential to ensure prompt diagnosis and resolve the diagnostic odyssey.\n <\/jats:p>","DOI":"10.1002\/jdn.70119","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T13:21:37Z","timestamp":1775049697000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Early\u2010Onset Hyperkinetic Movement Disorders Define the Most Severe Presentation of the\n ATP8A2<\/i>\n \u2010Related Phenotypic Spectrum"],"prefix":"10.1002","volume":"86","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4419-7381","authenticated-orcid":false,"given":"Fabio","family":"Bruschi","sequence":"first","affiliation":[{"name":"COALA (Center for Diagnosis and Treatment of Leukodystrophies), Unit of Pediatric Neurology Vittore Buzzi Children's Hospital Milan Italy"},{"name":"Department of Biomedical and Clinical Sciences Luigi Sacco Universit\u00e0 Degli Studi di Milano Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clara\u00a0E.","family":"Antonello","sequence":"additional","affiliation":[{"name":"COALA (Center for Diagnosis and Treatment of Leukodystrophies), Unit of Pediatric Neurology Vittore Buzzi Children's Hospital Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cecilia","family":"Parazzini","sequence":"additional","affiliation":[{"name":"Pediatric Radiology and Neuroradiology Department Vittore Buzzi Children's Hospital Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ylenia","family":"Vaia","sequence":"additional","affiliation":[{"name":"COALA (Center for Diagnosis and Treatment of Leukodystrophies), Unit of Pediatric Neurology Vittore Buzzi Children's Hospital Milan Italy"},{"name":"Department of Biomedical and Clinical Sciences Luigi Sacco Universit\u00e0 Degli Studi di Milano Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4707-212X","authenticated-orcid":false,"given":"Maria","family":"Iascone","sequence":"additional","affiliation":[{"name":"Medical Genetics Laboratory ASST Papa Giovanni XXIII Bergamo Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Davide","family":"Tonduti","sequence":"additional","affiliation":[{"name":"COALA (Center for Diagnosis and Treatment of Leukodystrophies), Unit of Pediatric Neurology Vittore Buzzi Children's Hospital Milan Italy"},{"name":"Department of Biomedical and Clinical Sciences Luigi Sacco Universit\u00e0 Degli Studi di Milano Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/mdc3.13820"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.13954"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10048\u2010024\u201000773\u20109"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/mdc3.12937"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415\u2010019\u201009579\u20104"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24180"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.5334\/tohm.548"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023\u2010018\u20100825\u20103"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1620\/tjem.2022.J010"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/WCO.0000000000000580"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002853"}],"container-title":["International Journal of Developmental 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