The GRIN1 gene encodes the subunit 1 of the N-methyl D-aspartate (NMDA) ionotropic glutamate receptor. It has an excitatory effect and it controls synaptic plasticity in the central nervous system. The gene is expressed in various neuronal cells throughout the brain, particularly in the hippocampus, cerebral cortex, and cerebellum. Experimental models suggest that dysfunction of NMDA receptors plays a role in malformation of cortical development.
We report a 3 year old infant male with severe psychomotor retardation, who presented in the first week of life with intractable neonatal seizures associated with primary microcephaly. He had multiple seizures per day characterized by clusters of facial grimacing, screaming and hand fisting. Anti-epileptic therapy with phenobarbital followed by vigabatrin, topiramate, clobazam and lamotrigine was ineffective. Better response with reduction in the frequency and intensity of the seizures was reached with ketogenic diet and later with steroid treatment. Sequential EEG records initially showed left temporal focus; subsequently bilateral multifocal epileptic discharges were found. Surprisingly the background activity was relatively preserved. It should be noted that despite the severity and drug-resistant seizures there were no clinical infantile spasms or EEG pattern of hypsarrhythmia.
Brain MRI, at 6 weeks of age, showed migration and sulcation disorder of the gray matter associated with bilateral fronto-parietal and temporal polymicrogyria, bilateral frontal band heterotropia, undeveloped hypocampus and hypomyelinization. Preliminary metabolic work-up was normal. It included blood chemistry tests, lactate, ammonia, blood gases, amino acids, organic acids, very long chain fatty acids and biotinidase. A whole exome sequence was performed and revealed a novel mutation (p. D789N c.2365G>A) in the GRIN1 gene.
Although mutations in GRIN1 were identified in cases of non-syndromic intellectual disability and recently non-inherited alterations in this gene were reported in cases of epileptic encephalopathy, we report for the first time a mutation which is associated with epilepsy related to malformations of brain development. Experimental animal models suggest the role of NMDA receptors in the development of the cerebral cortex and that their dysfunction plays a role in malformation of cortical development, especially in the migrational stage and epileptogenesis. Our report expands the clinical spectrum of GRIN1-associated neurological disorders, and suggests its possible link with developmental brain malformation and epilepsy
