Abstracts

Rationale: Recent progress in genetic analysis reveals that a significant part of cryptogenic epileptic encephalopathies is indeed single-gene disorders. 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: Four patients with de novo missense GRIN1 mutations with unclassified epilepsy were ascertained. Clinical histories, neurological examinations, neurophysiological and neuroradiological data, and results of genetic analysis were obtained. Clinical phenotypes including epilepsy were evaluated. The effect of mutations on N-methyl-D aspartate receptors was examined by mapping altered amino acids onto three-dimensional models.Results: 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 only exhibited 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 N-methyl-D aspartate receptor.Conclusions: 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, mimicking neurotransmitter disease.