Electroclinical history of a five‐year‐old girl with GRIN1‐related early‐onset epileptic encephalopathy: a video‐case study

Abstract

De novo mutations in the GRIN1 gene have been recently reported as the molecular cause of a broad-spectrum early-onset neurological phenotype. Here, we describe a five-year-old girl with an early-onset epileptic encephalopathy associated with an infantile hyperkinetic movement disorder and oculomotor abnormalities. Whole-exome sequencing identified a novel p.Met641Leu de novo variant in the GRIN1 gene as the cause of the phenotype. In silico analysis suggested that the p.Met641Leu variant would alter the gating property of the ion channel, with the involved methionine residue facing towards the ion pore. Long-term systematic video-EEG allowed us to report on the electroclinical history and, specifically, on the semiology of the hyperkinetic movement disorder and oculomotor abnormalities resembling oculogyric crises in our patient. Our findings and a review of the recent literature reinforce the notion of GRIN1encephalopathy as a recognizable neurological phenotype that should be suspected in early-onset epilepsy associated with hyperkinetic movement disorders. [Published with video sequence on www.epilepticdisorders.com]

West syndrome with hyperkinesia and cortical visual impairment: A case report of GRIN1 encephalopathy

“…The hyperkinetic movements in our proband were gradually ameliorated after the seizures subsided, and they were minimal at 23 months of age. In a single case reported by Pironiti et al [13], abnormal movements were observed evidently during infancy and less prominently at five years of age. Data regarding the prognosis of movement disorders are limited.…”

“…Concerning the genotype-phenotype correlation, the GRIN1 mutations in the patients with extensive bilateral polymicrogyria have been found to be located in M3 or S2, with the patients exhibiting severe phenotypes, including intractable epilepsy, cortical blindness, microcephaly, profound delay, and spastic tetraplegia [11,12]. Heterozygous de novo mutations have been reported in most patients with GRIN1-NDHMS; however, homozygous mutations have also been detected in some patients [5][6][7][8][9][10][11][12][13][14]. Most GRIN1 mutations result in a loss of function [5][6][7][8][9][10][11][12][13][14][15].…”

“…Mutations of the gene encoding the glutamate receptor ionotropic N-methyl-D-aspartate (NMDA) subunit 1 (GRIN1) result in neurodevelopmental disorders with or without hyperkinetic movements and seizures (NDHMS) [5][6][7][8][9][10][11][12][13][14][15]. NMDA receptors are ligand-gated ion channels composed of two glycinebinding subunits (GluN1) and two glutamate-binding subunits; the GluN1 subunit is encoded by GRIN1 [5][6][7][8][9][10][11]14,15].…”

“…All individuals with GRIN1-NDHMS demonstrate developmental delay from early infancy and have a non-syndromic intellectual disability [5][6][7][8][9][10][11][12][13]. In addition to epileptic seizures, abnormal movement disorders and cortical visual impairment have been reported to be characteristic in patients with GRIN1 encepha-lopathy, although their prognoses have not been determined yet [5][6][7][8][9][10][11][12][13][14]16]. Some patients with GRIN1 mutations demonstrate autistic features and polymicrogyria [9,11,12].…”

Spotlight on Oculogyric Crisis: A Review

“…18,19 PLA2G6 associated neurodegeneration (PLAN), which occurs due to a homozygous mutation of PLA2G6, is a rare cause of OGC. 20 Some neurodegenerative disorders are also found to be associated with the occurrence of OGC, such as mutations in the GRIN1 gene, which affects the function of both N-methyl-D-aspartate and dopamine D1 receptors, leading to oculomotor dystonic reactions; 21,22 Neuronal intranuclear hyaline inclusion disease, a multisystem degenerative disorder that involves both central and peripheral nervous systems, causing diffuse muscle spasms, dysarthria, dysphagia, tremors, ataxia, OGC, progressive muscle weakness, and atrophy 23 ; Rett syndrome, progressive neurodegenerative disorder in females, leads to gait disturbance, bruxism, OGC, parkinsonism, and dystonia 24 and tyrosine hydroxylase (TOH) deficiency, an inborn error of catecholamine biosynthesis causing dystonia along with tremor, hypersensitivity to levodopa therapy, OGC, akinesia, and rigidity. 25,26 Other autosomal recessive disorders that rarely present with OGC are Kufor Rakeb, 27 haemophagocytic lymphohistiocytosis, 28 sepiapterin reductase deficiency, 29,30 and GTP cyclohydrolase I deficiency.…”