Identification of <em>ATP1A3</em> Mutations by Exome Sequencing as the Cause of Alternating Hemiplegia of Childhood in Japanese Patients

<div><h3>Background</h3><p>Alternating hemiplegia of childhood (AHC) is a rare disorder characterized by transient repeated attacks of paresis and cognitive impairment. Recent studies from the U.S. and Europe have described <em>ATP1A3</em> mutations in AHC. However, the genotype-phenotype relationship remains unclear. The purpose of this study was to identify the genetic abnormality in a Japanese cohort of AHC using exome analysis.</p> <h3>Principal Findings</h3><p>A total of 712,558 genetic single nucleotide variations in 8 patients with sporadic AHC were found. After a series of exclusions, mutations of three genes were regarded as candidate causes of AHC. Each patient harbored a heterozygous missense mutation of <em>ATP1A3</em>, which included G755C, E815K, C927Y and D801N. All mutations were at highly conserved amino acid residues and deduced to affect ATPase activity of the corresponding ATP pump, the product of <em>ATP1A3</em>. They were <em>de novo</em> mutations and not identified in 96 healthy volunteers. Using Sanger sequencing, E815K was found in two other sporadic cases of AHC. In this study, E815K was found in 5 of 10 patients (50%), a prevalence higher than that reported in two recent studies [19 of 82 (23%) and 7 of 24 (29%)]. Furthermore, the clinical data of the affected individuals indicated that E815K resulted in a severer phenotype compared with other <em>ATP1A3</em> mutations.</p> <h3>Interpretation</h3><p>Heterozygous <em>de novo</em> mutations of <em>ATP1A3</em> were identified in all Japanese patients with AHC examined in this study, confirming that <em>ATP1A3</em> mutation is the cause of AHC.</p>