Chihiro Ohba1,2, Masaaki Shiina3, Jun Tohyama4, Kazuhiro Haginoya5, Tally Lerman-Sagie6, Nobuhiko Okamoto7, Lubov Blumkin6, Dorit Lev6, Souichi Mukaida8, Fumihito Nozaki9, Mitsugu Uematsu10, Akira Onuma11, Hirofumi Kodera1, Mitsuko Nakashima1, Yoshinori Tsurusaki1, Noriko Miyake1, Fumiaki Tanaka2, Mitsuhiro Kato12, Kazuhiro Ogata3, Hirotomo Saitsu1, Naomichi Matsumoto1. 1. Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Yokohama, Japan. 2. Department of Clinical Neurology and Stroke Medicine, Yokohama City University, Yokohama, Japan. 3. Department of Biochemistry, Graduate School of Medicine, Yokohama City University, Yokohama, Japan. 4. Department of Pediatrics, Epilepsy Center, Nishi-Niigata Chuo National Hospital, Niigata, Japan. 5. Department of Pediatric Neurology, Takuto Rehabilitation Center for Children, Sendai, Japan. 6. Metabolic Neurogenetic Clinic, Wolfson Medical Center, Holon, Israel. 7. Department of Medical Genetics, Osaka Medical Center, Research Institute for Maternal and Child Health, Osaka, Japan. 8. Department of Pediatric Neurology, National Hospital Organization Utano Hospital, Kyoto, Japan. 9. Department of Pediatrics, Shiga Medical Center for Children, Shiga, Japan. 10. Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan. 11. Department of Pediatrics, Ekoh-Ryoikuen, Sendai, Japan. 12. Department of Pediatrics, Faculty of Medicine, Yamagata University, Yamagata, Japan.
Abstract
OBJECTIVE: Recently, de novo mutations in GRIN1 have been identified in patients with nonsyndromic intellectual disability and epileptic encephalopathy. Whole exome sequencing (WES) analysis of patients with genetically unsolved epileptic encephalopathies identified four patients with GRIN1 mutations, allowing us to investigate the phenotypic spectrum of GRIN1 mutations. METHODS: Eighty-eight patients with unclassified early onset epileptic encephalopathies (EOEEs) with an age of onset <1 year were analyzed by WES. The effect of mutations on N-methyl-D-aspartate (NMDA) receptors was examined by mapping altered amino acids onto three-dimensional models. RESULTS: We identified four de novo missense GRIN1 mutations in 4 of 88 patients with unclassified EOEEs. In these four patients, initial symptoms appeared within 3 months of birth, including hyperkinetic movements in two patients (2/4, 50%), and seizures in two patients (2/4, 50%). Involuntary movements, severe developmental delay, and intellectual disability were recognized in all four patients. In addition, abnormal eye movements resembling oculogyric crises and stereotypic hand movements were observed in two and three patients, respectively. All the four patients exhibited only nonspecific focal and diffuse epileptiform abnormality, and never showed suppression-burst or hypsarrhythmia during infancy. A de novo mosaic mutation (c.1923G>A) with a mutant allele frequency of 16% (in DNA of blood leukocytes) was detected in one patient. Three mutations were located in the transmembrane domain (3/4, 75%), and one in the extracellular loop near transmembrane helix 1. All the mutations were predicted to impair the function of the NMDA receptor. SIGNIFICANCE: Clinical features of de novo GRIN1 mutations include infantile involuntary movements, seizures, and hand stereotypies, suggesting that GRIN1 mutations cause encephalopathy resulting in seizures and movement disorders. Wiley Periodicals, Inc.
OBJECTIVE: Recently, de novo mutations in GRIN1 have been identified in patients with nonsyndromic intellectual disability and epileptic encephalopathy. Whole exome sequencing (WES) analysis of patients with genetically unsolved epileptic encephalopathies identified four patients with GRIN1 mutations, allowing us to investigate the phenotypic spectrum of GRIN1 mutations. METHODS: Eighty-eight patients with unclassified early onset epileptic encephalopathies (EOEEs) with an age of onset <1 year were analyzed by WES. The effect of mutations on N-methyl-D-aspartate (NMDA) receptors was examined by mapping altered amino acids onto three-dimensional models. RESULTS: We identified four de novo missense GRIN1 mutations in 4 of 88 patients with unclassified EOEEs. In these four patients, initial symptoms appeared within 3 months of birth, including hyperkinetic movements in two patients (2/4, 50%), and seizures in two patients (2/4, 50%). Involuntary movements, severe developmental delay, and intellectual disability were recognized in all four patients. In addition, abnormal eye movements resembling oculogyric crises and stereotypic hand movements were observed in two and three patients, respectively. All the four patients exhibited only nonspecific focal and diffuse epileptiform abnormality, and never showed suppression-burst or hypsarrhythmia during infancy. A de novo mosaic mutation (c.1923G>A) with a mutant allele frequency of 16% (in DNA of blood leukocytes) was detected in one patient. Three mutations were located in the transmembrane domain (3/4, 75%), and one in the extracellular loop near transmembrane helix 1. All the mutations were predicted to impair the function of the NMDA receptor. SIGNIFICANCE: Clinical features of de novo GRIN1 mutations include infantile involuntary movements, seizures, and hand stereotypies, suggesting that GRIN1 mutations cause encephalopathy resulting in seizures and movement disorders. Wiley Periodicals, Inc.
Authors: Esther A R Nibbeling; Cathérine C S Delnooz; Tom J de Koning; Richard J Sinke; Hyder A Jinnah; Marina A J Tijssen; Dineke S Verbeek Journal: Neurosci Biobehav Rev Date: 2017-01-28 Impact factor: 8.989
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Authors: Dong Li; Hongjie Yuan; Xilma R Ortiz-Gonzalez; Eric D Marsh; Lifeng Tian; Elizabeth M McCormick; Gabrielle J Kosobucki; Wenjuan Chen; Anthony J Schulien; Rosetta Chiavacci; Anel Tankovic; Claudia Naase; Frieder Brueckner; Celina von Stülpnagel-Steinbeis; Chun Hu; Hirofumi Kusumoto; Ulrike B S Hedrich; Gina Elsen; Konstanze Hörtnagel; Elias Aizenman; Johannes R Lemke; Hakon Hakonarson; Stephen F Traynelis; Marni J Falk Journal: Am J Hum Genet Date: 2016-09-08 Impact factor: 11.025