title: De novo p.Arg756Cys mutation of ATP1A3 causes an atypical form of alternating hemiplegia of childhood with prolonged paralysis and choreoathetosis.
abstract: BACKGROUND
  Alternating hemiplegia of childhood (AHC) is a rare neurological disorder that manifests recurrent attacks of hemiplegia, oculogyric, and choreoathetotic involuntary movements. De novo mutations in ATP1A3 cause three types of neurological diseases: AHC; rapid-onset dystonia-Parkinsonism (RDP); and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndromes. It remains to be determined whether or not a rare mutation in ATP1A3 may cause atypical phenotypes.
  
  
  METHODS
  A 7-year-old boy presented with recurrent symptoms of generalized paralysis since 1 year and 5 months of age. Hypotonia, dystonia, and choreoathetosis persisted with exacerbation under febrile conditions, but no cerebellar ataxia had ever evolved in 6 years. Whole-exome sequencing (WES) was performed to determine his genetic background, and mutations were validated by the Sanger method. Crude protein extracts were prepared from the cultured cells, and expression of the wild-type or mutant ATP1A3 proteins were analyzed by Western blotting. WES identified a de novo pathogenic mutation in ATP1A3 (c.2266C > T:p.R756C) for this patient. A literature overview of two reported cases with p.R756C and p.R756H mutations showed both overlapping and distinct phenotypes when compared with those of the present case. The expression of the mutant form (R756C) of ATP1A3 did not differ markedly from that of the wild-type and D801N proteins.
  
  
  CONCLUSIONS
  This study confirmed that p.R756C mutation of ATP1A3 cause atypical forms of AHC-associated disorders. The wide spectra of neurological phenotypes in AHC are linked to as-yet-unknown deficits in the functions of mutant ATP1A3.
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Kanemasa
authors.affiliation: Department of Human Genetics, Yokohama City University School of Medicine, Yokohama, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Fukai
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. ysakai22q13@gmail.com.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Torio
authors.affiliation: Department of Human Genetics, Yokohama City University School of Medicine, Yokohama, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.|Present address: Fukuoka Children's Hospital, Fukuoka, Japan.
authors.forename: Sooyoung
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ono
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Akamine
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Nishiyama
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Sanefuji
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Ishizaki
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.|Present address: Section of Pediatrics, Department of Medicine, Fukuoka Dental College, Fukuoka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Torisu
authors.affiliation: Department of Human Genetics, Yokohama City University School of Medicine, Yokohama, Japan.|Present address: Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.affiliation: Department of Human Genetics, Yokohama City University School of Medicine, Yokohama, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.|Present address: Fukuoka Children's Hospital, Fukuoka, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hara
mesh_terms: D001264:Athetosis / Q000150:complications* / Q000235:genetics*; D002648:Child; D002819:Chorea / Q000150:complications / Q000235:genetics*; D006429:Hemiplegia / Q000150:complications* / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010243:Paralysis / Q000150:complications / Q000235:genetics*; D010641:Phenotype; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics*
chemical_list: C488756:ATP1A3 protein, human; D000254:Sodium-Potassium-Exchanging ATPase
keywords: ATP1A3; Alternating hemiplegia of childhood; Areflexia; Optic atrophy and sensorineural hearing loss; Rapid-onset dystonia-Parkinsonism; Whole-exome sequencing