Expanding the Phenotypic Spectrum of GRIN1 Encephalopathy: Two Pediatric Patients with Atypical Findings

Abstract

Introduction GRIN1 encephalopathy is an emerging genetic entity due to de novomonoallelic or biallelic pathogenic variants in the GRIN1 gene that impair the functionof the GluN1 subunit of the N-methyl-D-aspartate (NMDA) receptor. Here, we describetwo patients with GRIN1 encephalopathy with an uncommon neuroradiologicalpattern.Cases Presentation Two boys presented with a neurodevelopmental disorder characterized by severe cognitive impairment, autistic features, hand stereotyped movements, self-injurious behavior, and hyperkinetic movements. They were nonverbal anddid not acquire the ability to walk. Both developed epileptic encephalopathy withepileptic spasms. Magnetic resonance imaging of the brain showed bilateral hippocampal sclerosis in both, and one of them showed multiple cortical lesions withdiffusion restriction. Two relevant missense variants in the GRIN1 gene were identifiedby a next-generation sequencing panel, one was novel (c.1927A >G-p.(Ile643Val)) andthe other (c.2530C > T-p.(Arg844Cys)) was previously reported associated with GRIN1-neurodevelopmental disorder. Both variants are predicted to affect the normalfunction of the GluN1 subunit and were classified as likely pathogenic and pathogenic,respectively.Conclusion The association of severe cognitive impairment, autistic features withhand stereotypies, self-injurious behavior, and hyperkinetic movements in patientswith epileptic encephalopathy are characteristic of GRIN1 encephalopathy. The hippocampal sclerosis and cortical lesions, similar to those found in NMDA autoimmuneencephalitis, observed in these patients expand the neuroradiological features of thisentity.