Neuropediatrics 2013; 44 - FV15_03
DOI: 10.1055/s-0033-1337740

Alternating hemiplegia of childhood is caused by heterozygous de novo mutations in the ATP1A3 gene: The expanding mutational spectrum of ATP1A3-related dystonic movement disorders

H Rosewich 1, H Thiele 2, A Ohlenbusch 1, M Hillebrand 1, S Schröder 1, U Maschke 3, P Huppke 1, P Nürnberg 2, K Brockmann 1, J Gärtner 1
  • 1Georg-August-Universität Göttingen, Klinik für Kinder-und Jugendmedizin, Göttingen, Germany
  • 2Cologne Center for Genomics (CCG) and Institute for Genetics, University of Cologne, Köln, Germany
  • 3Catholic Hospital St. Johann Nepomuk, Erfurt, Germany

Aims: Alternating hemiplegia of childhood (AHC) is a rare neurological disorder characterized by early onset of hemiplegic episodes, dystonia, and developmental impairment. Besides few cases of concordance in monozygotic twins and dominant transmission in families with milder phenotype, AHC is almost exclusively sporadic. The aim of the study is to identify de novo mutations associated with the disease.

Methods: Between 2004 and 2012, 24 AHC patients were recruited based on diagnostic criteria from Goutières et al 1993. Three families were chosen for proband-parent trio-based whole-exome sequencing. The whole exome from the healthy parents in each family was compared with the whole exome of their affected child. The candidate gene list (4 to 6 genes per trio) was then screened for overlapping genes in all three families, with only one gene displaying three different missense mutations in all the three affected children. We performed Sanger sequencing in the remaining 21 AHC patients, subsequently. Identified mutations were then analyzed for their pathogenicity with a cell survival assay and compared with already published and new mutations in the ATP1A3 gene in patients with rapid-onset dystonia-parkinsonism (RDP).

Results: The proband-parent trio-based whole-exome sequencing strategy revealed three different heterozygous de novo missense mutations only in the ATP1A3 gene in all the three affected children. Sanger sequencing of the remaining 21 AHC patients detected ATP1A3 mutation in each patient confirming the association between ATP1A3 gene mutations and AHC. All mutations were then analyzed in a cell survival assay. None of the mutants was able to restore wild-type function. Further analyses of identified mutations of our AHC patients, two own RDP patients, and all RDP patients published in the literature showed that mutations were distributed of the entire gene affecting different functional and conserved domains as well as different transmembrane regions of the protein.

Conclusion: AHC is caused by heterozygous de novo mutations in the ATP1A3 gene.