ATP1A2- and ATP1A3- associated early profound epileptic encephalopathy and polymicrogyria

作者：Annalisa Vetro, Hang N. Nielsen, Rikke Holm, Robert F. Hevner, Elena Parrini, Zöe Powis, Rikke S. Møller, Cristina Bellan, Alessandro Simonati, Gaëtan Lesca, Katherine L. Helbig, Elizabeth E. Palmer, Davide Mei, Elisa Ballardini, Arie van Haeringen, Steffen Syrbe, Vincenzo Leuzzi, Giovanni Cioni, Cynthia J. Curry, Gregory Costain, Margherita Santucci, Karen Chong, Grazia M.S. Mancini, Jill Clayton‐Smith, Stefania Bigoni, Ingrid E. Scheffer, William B. Dobyns, Bente Vilsen, Renzo Guerrini, ATP1A2/A3-collaborators, Damien Sanlaville, Rani Sachdev, Ian Andrews, Francesco Mari, A Cavalli, Carmen Barba, Beatrice De Maria, Giampaolo Garani, Johannes R. Lemke, Mario Mastrangelo, Emily Tam, Elizabeth Donner, Helen M. Branson, Fabíola Paoli Monteiro, Fernando Kok, Katherine B. Howell, Stephanie L. Leech, Heather C. Mefford, Alison M. Muir · 发表于：Brain · 年份：2021 · DOI：10.1093/brain/awab052 · 被引用次数：67 · 研究领域：Epilepsy research and treatment、Ion Transport and Channel Regulation、Metabolism and Genetic Disorders

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' 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...