De novo mutations in ATP1A3 cause alternating hemiplegia of childhood

Erin L. Heinzen, Kathryn J. Swoboda, Yuki Hitomi, Fiorella Gurrieri, Boukje De Vries, F. Danilo Tiziano, Bertrand Fontaine, Nicole M. Walley, Sinéad Heavin, Eleni Panagiotakaki, Stefania Fiori, Emanuela Abiusi, Lorena Di Pietro, Matthew T. Sweney, Tara M. Newcomb, Louis Viollet, Chad Huff, Lynn B. Jorde, Sandra P. Reyna, Kelley J. MurphyKevin V. Shianna, Curtis E. Gumbs, Latasha Little, Kenneth Silver, Louis J. Ptáček, Joost Haan, Michel D. Ferrari, Ann M. Bye, Geoffrey K. Herkes, Charlotte M. Whitelaw, David Webb, Bryan J. Lynch, Peter Uldall, Mary D. King, Ingrid E. Scheffer, Giovanni Neri, Alexis Arzimanoglou, Arn M J M Van Den Maagdenberg, Sanjay M. Sisodiya, Mohamad A. Mikati, David B. Goldstein, Stephany Koelewijn, Jessica Kamphorst, Marije Geilenkirchen, Nadine Pelzer, Michel Ferrari, Arn Van Den Maagdenberg, Claudio Zucca, Filippo Franchini, Rosaria Vavassori, Melania Giannotta, Giuseppe Gobbi, Tiziana Granata, Nardo Nardocci, Elisa De Grandis, Edvige Veneselli, Michela Stagnaro, Federico Vigevano, Claudia Oechsler, Sophie Nicole, Miriam Ninan, Brian Neville, Friedrich Ebinger, Carmen Fons, Jaume Campistol, David Kemlink, Sona Nevsimalova, Laura Laan, Cacha Peeters-Scholte, Paul Casaer, Giorgio Casari, Guenter Sange, Georg Spiel, Filippo Martinelli Boneschi, Maria Teresa Bassi, Tsveta Schyns, Francis Crawley, Dominique Poncelin

Research output: Contribution to journalArticlepeer-review


Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequencing of seven patients with AHC and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals. In a subsequent sequence analysis of ATP1A3 in 98 other patients with AHC, we found that ATP1A3 mutations were likely to be responsible for at least 74% of the cases; we also identified one inherited mutation in a case of familial AHC. Notably, most AHC cases are caused by one of seven recurrent ATP1A3 mutations, one of which was observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset dystonia-parkinsonism, AHC-causing mutations in this gene caused consistent reductions in ATPase activity without affecting the level of protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3.

Original languageEnglish
Pages (from-to)1030-1034
Number of pages5
JournalNature Genetics
Issue number9
Publication statusPublished - Sep 2012

ASJC Scopus subject areas

  • Genetics

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