{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T03:55:48Z","timestamp":1792468548486,"version":"4.5.0"},"reference-count":60,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2021,5,1]],"date-time":"2021-05-01T00:00:00Z","timestamp":1619827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100003554","name":"Lundbeck Foundation","doi-asserted-by":"publisher","award":["R223-2016-595"],"award-info":[{"award-number":["R223-2016-595"]}],"id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008392","name":"Danish Medical Research Council","doi-asserted-by":"publisher","award":["7016-00193B"],"award-info":[{"award-number":["7016-00193B"]}],"id":[{"id":"10.13039\/100008392","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011102","name":"European Union Seventh Framework Programme","doi-asserted-by":"publisher","award":["FP7\/2013"],"award-info":[{"award-number":["FP7\/2013"]}],"id":[{"id":"10.13039\/100011102","id-type":"DOI","asserted-by":"publisher"}]},{"name":"DESIRE","award":["602531"],"award-info":[{"award-number":["602531"]}]},{"name":"Italian Ministry of Health and Tuscany Region","award":["RF-2013-02355240"],"award-info":[{"award-number":["RF-2013-02355240"]}]},{"name":"Tuscany Region Call for Health 2018"},{"name":"National Health and Medical Research Council of Australia","award":["APP1091593"],"award-info":[{"award-number":["APP1091593"]}]},{"name":"National Health and Medical Research Council of Australia","award":["APP1104831"],"award-info":[{"award-number":["APP1104831"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,6,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Constitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct isoforms of the Na+\/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic migraine (ATP1A2), alternating hemiplegia of childhood (ATP1A2\/A3), rapid-onset dystonia-parkinsonism, cerebellar ataxia-areflexia-progressive optic atrophy, and relapsing encephalopathy with cerebellar ataxia (all ATP1A3). A few reports have described single individuals with heterozygous mutations of ATP1A2\/A3 associated with severe childhood epilepsies. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2. We investigated the genetic causes of developmental and epileptic encephalopathies variably associated with malformations of cortical development in a large cohort and identified 22 patients with de novo or inherited heterozygous ATP1A2\/A3 mutations. We characterized clinical, neuroimaging and neuropathological findings, performed in silico and in vitro assays of the mutations\u2019 effects on the NKA-pump function, and studied genotype-phenotype correlations. Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual). Polymicrogyria occurred in 10 (45%) patients, showing a mainly bilateral perisylvian pattern. Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. A distinctive, \u2018profound\u2019 phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). In silico evaluation predicted all mutations to be detrimental. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. Genotype-phenotype analysis suggested a link between the most severe phenotypes and lack of COS-1 cell survival, and also revealed a wide continuum of severity distributed across mutations that variably impair NKA-pump activity. We performed neuropathological analysis of the whole brain in two individuals with polymicrogyria respectively related to a heterozygous ATP1A3 mutation and a homozygous ATP1A2 mutation and found close similarities with findings suggesting a mainly neural pathogenesis, compounded by vascular and leptomeningeal abnormalities. Combining our report with other studies, we estimate that \u223c5% of mutations in ATP1A2 and 12% in ATP1A3 can be associated with the severe and novel phenotypes that we describe here. Notably, a few of these mutations were associated with more than one phenotype. These findings assign novel, \u2018profound\u2019 and early lethal phenotypes of developmental and epileptic encephalopathies and polymicrogyria to the phenotypic spectrum associated with heterozygous ATP1A2\/A3 mutations and indicate that severely impaired NKA pump function can disrupt brain morphogenesis.<\/jats:p>","DOI":"10.1093\/brain\/awab052","type":"journal-article","created":{"date-parts":[[2021,2,10]],"date-time":"2021-02-10T20:35:10Z","timestamp":1612989310000},"page":"1435-1450","source":"Crossref","is-referenced-by-count":75,"title":["<i>ATP1A2-<\/i> and <i>ATP1A3-<\/i>associated early profound epileptic encephalopathy and polymicrogyria"],"prefix":"10.1093","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2437-7526","authenticated-orcid":false,"given":"Annalisa","family":"Vetro","sequence":"first","affiliation":[{"name":"Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, University of Florence, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang N","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rikke","family":"Holm","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University, DK-8000, Aarhus C, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert F","family":"Hevner","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California San Diego, San Diego, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Parrini","sequence":"additional","affiliation":[{"name":"Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, University of Florence, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoe","family":"Powis","sequence":"additional","affiliation":[{"name":"Ambry Genetics, Aliso Viejo, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rikke S","family":"M\u00f8ller","sequence":"additional","affiliation":[{"name":"Department of Epilepsy Genetics and Personalized Medicine Danish Epilepsy Centre, Filadelfia, Denmark"},{"name":"Department of Regional Health Services, University of Southern Denmark, Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Bellan","sequence":"additional","affiliation":[{"name":"Department of Neonatal Intensive Care Unit, Bolognini Hospital, ASST-Bergamo Est, Seriate, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Simonati","sequence":"additional","affiliation":[{"name":"Neurology (Child Neurology and Neuropathology), Department of Neuroscience, Biomedicine and Movement, University of Verona, Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ga\u00e9tan","family":"Lesca","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Member of the ERN EpiCARE, University Hospital of Lyon, Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8249-0549","authenticated-orcid":false,"given":"Katherine L","family":"Helbig","sequence":"additional","affiliation":[{"name":"Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth E","family":"Palmer","sequence":"additional","affiliation":[{"name":"Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, NSW, Australia"},{"name":"School of Women's and Children's Health, University of New South Wales, Randwick, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Mei","sequence":"additional","affiliation":[{"name":"Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, University of Florence, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Ballardini","sequence":"additional","affiliation":[{"name":"Neonatal Intensive Care Unit, Pediatric Section, Department of Medical Sciences, Ferrara University, Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arie","family":"Van Haeringen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Syrbe","sequence":"additional","affiliation":[{"name":"Division of Pediatric Epileptology, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Leuzzi","sequence":"additional","affiliation":[{"name":"Department of Human Neuroscience, Unit of Child Neurology and Psychiatry, Sapienza University, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Cioni","sequence":"additional","affiliation":[{"name":"Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia J","family":"Curry","sequence":"additional","affiliation":[{"name":"Genetic Medicine, Department of Pediatrics, University of California, San Francisco\/Fresno, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Costain","sequence":"additional","affiliation":[{"name":"Division of Clinical and Metabolic Genetics, Department of Pediatrics, The 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Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill","family":"Clayton-Smith","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine, University of Manchester, St Mary's Hospital, Manchester, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Bigoni","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Department of Mother and Child, Ferrara University Hospital, Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid E","family":"Scheffer","sequence":"additional","affiliation":[{"name":"University of Melbourne, Austin Health and Royal Children's Hospital, Florey and Murdoch Institutes, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7681-2844","authenticated-orcid":false,"given":"William B","family":"Dobyns","sequence":"additional","affiliation":[{"name":"Department of 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