GRIN1 mutations cause encephalopathy with infantile‐onset epilepsy, and hyperkinetic and stereotyped movement disorders. (10th April 2015)

• Record Type: Journal Article
• Authors: Ohba, Chihiro; Shiina, Masaaki; Tohyama, Jun; Haginoya, Kazuhiro; Lerman‐Sagie, Tally; Okamoto, Nobuhiko; Blumkin, Lubov; Lev, Dorit; Mukaida, Souichi; Nozaki, Fumihito; Uematsu, Mitsugu; Onuma, Akira; Kodera, Hirofumi; Nakashima, Mitsuko; Tsurusaki, Yoshinori; Miyake, Noriko; Tanaka, Fumiaki; Kato, Mitsuhiro; Ogata, Kazuhiro; Saitsu, Hirotomo; Matsumoto, Naomichi
• Is Part Of: Epilepsia. Volume 56:issue 6(2015:Jun.)
• Page Start: 841
• Page End: 848
• Publication Date: 2015-04-10
• Subjects: Epilepsy -- Periodicals; 616.853
• DOI: 10.1111/epi.12987
• Languages: English
• ISSNs: 0013-9580

Abstract

<abstract abstract-type="main" id="epi12987-abs-0001"> <title>Summary</title> <sec id="epi12987-sec-0001" sec-type="section"> <title>Objective</title> <p>Recently, de novo mutations in <italic>GRIN1</italic> 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 <italic>GRIN1</italic> mutations, allowing us to investigate the phenotypic spectrum of <italic>GRIN1</italic> mutations.</p> </sec> <sec id="epi12987-sec-0002" sec-type="section"> <title>Methods</title> <p>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 <italic>N</italic>‐methyl‐<sc>d</sc>‐aspartate (NMDA) receptors was examined by mapping altered amino acids onto three‐dimensional models.</p> </sec> <sec id="epi12987-sec-0003" sec-type="section"> <title>Results</title> <p>We identified four de novo missense <italic>GRIN1</italic> 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.</p> </sec> <sec id="epi12987-sec-0004" sec-type="section"> <title>Significance</title> <p>Clinical features of de novo <italic>GRIN1</italic> mutations include infantile involuntary movements, seizures, and hand stereotypies, suggesting that <italic>GRIN1</italic> mutations cause encephalopathy resulting in seizures and movement disorders.</p> </sec> </abstract>