title: The first report of Japanese patients with asparagine synthetase deficiency.
abstract: BACKGROUND
  Asparagine synthetase (ASNS) deficiency was recently discovered as a metabolic disorder of non-essential amino acids, and presents as severe progressive microcephaly, intellectual disorder, dyskinetic quadriplegia, and intractable seizures.
  
  
  METHODS
  Two Japanese children with progressive microcephaly born to unrelated patients were analyzed by whole exome sequencing and novel ASNS mutations were identified. The effects of the ASNS mutations were analyzed by structural evaluation and in silico predictions.
  
  
  RESULTS
  We describe the first known Japanese patients with ASNS deficiency. Their clinical manifestations were very similar to reported cases of ASNS deficiency. Progressive microcephaly was noted during the prenatal period in patient 1 but only after birth in patient 2. Both patients had novel ASNS mutations: patient 1 had p.L145S transmitted from his mother and p.L247W which was absent from his mother, while patient 2 carried p.V489D and p.W541Cfs*5, which were transmitted from his mother and father, respectively. Three of the four mutations were predicted to affect protein folding, and in silico analyses suggested that they would be pathogenic.
  
  
  CONCLUSIONS
  We report the first two Japanese patients with ASNS deficiency. Disease severity appears to vary among patients, as is the case for other non-essential amino acid metabolic disorders.
authors.affiliation: Department of Disability Medicine, Graduate School of Medicine, Gifu University, Gifu, Japan; Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan. Electronic address: tyamamo@gifu-u.ac.jp.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Sendai, Japan.
authors.forename: Wakaba
authors.initials: W
authors.lastname: Endo
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ohnishi
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kubota
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Kawamoto
authors.affiliation: Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Sendai, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Inui
authors.affiliation: Department of Pediatrics, Gifu Prefectural General Medical Center, Gifu, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Imamura
authors.affiliation: Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Takanashi
authors.affiliation: Department of Biochemistry, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Shiina
authors.affiliation: Department of Human Genetics, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.affiliation: Department of Biochemistry, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogata
authors.affiliation: Department of Human Genetics, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Sendai, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Haginoya
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Fukao
mesh_terms: D044466:Asian People; D001217:Aspartate-Ammonia Ligase / Q000172:deficiency*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010375:Pedigree
chemical_list: D001217:Aspartate-Ammonia Ligase
keywords: Asparagine synthetase deficiency; Cerebral atrophy; Developmental delay; Intractable seizures; Microcephaly; Non-essential amino acid metabolic disorder