In:
Epilepsia, Wiley, Vol. 56, No. 6 ( 2015-06), p. 841-848
Abstract:
Recently, de novo mutations in GRIN 1 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 GRIN 1 mutations, allowing us to investigate the phenotypic spectrum of GRIN 1 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 GRIN 1 mutations in 4 of 88 patients with unclassified EOEE s. 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 GRIN 1 mutations include infantile involuntary movements, seizures, and hand stereotypies, suggesting that GRIN 1 mutations cause encephalopathy resulting in seizures and movement disorders.
Type of Medium:
Online Resource
ISSN:
0013-9580
,
1528-1167
DOI:
10.1111/epi.2015.56.issue-6
Language:
English
Publisher:
Wiley
Publication Date:
2015
detail.hit.zdb_id:
216382-2
detail.hit.zdb_id:
2002194-X
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