Takahiro Yamamoto1, Wakaba Endo2, Hidenori Ohnishi3, Kazuo Kubota3, Norio Kawamoto3, Takehiko Inui2, Atsushi Imamura4, Jun-Ichi Takanashi5, Masaaki Shiina6, Hirotomo Saitsu7, Kazuhiro Ogata6, Naomichi Matsumoto7, Kazuhiro Haginoya2, Toshiyuki Fukao3. 1. 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. 2. Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Sendai, Japan. 3. Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan. 4. Department of Pediatrics, Gifu Prefectural General Medical Center, Gifu, Japan. 5. Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan. 6. Department of Biochemistry, Yokohama City University, Graduate School of Medicine, Yokohama, Japan. 7. Department of Human Genetics, Yokohama City University, Graduate School of Medicine, Yokohama, Japan.
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. CONCLUSION: 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.
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. CONCLUSION: 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.
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