• Erin L Heinzen, Kathryn J Swoboda, Yuki Hitomi, Fiorella Gurrieri, Sophie Nicole, Boukje de Vries, F Danilo Tiziano, Bertrand Fontaine, Nicole M Walley, Sinéad Heavin, Eleni Panagiotakaki, European Alternating Hemiplegia of Childhood (AHC) Genetics Consortium, Biobanca e Registro Clinico per l'Emiplegia Alternante (I.B.AHC) Consortium, European Network for Research on Alternating Hemiplegia (ENRAH) for Small and Medium-sized Enterpriese (SMEs) Consortium, 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 Murphy, Kevin 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, and David B Goldstein.
• Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, USA.
• Nat. Genet. 2012 Sep 1;44(9):1030-4.

AbstractAlternating 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.

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