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 novo monoallelic or biallelic pathogenic variants in the GRIN1 gene that impair the function of the GluN1 subunit of the N-methyl-D-aspartate (NMDA) receptor. Here, we describe two patients with GRIN1 encephalopathy with an uncommon neuroradiological pattern. 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 and did not acquire the ability to walk. Both developed epileptic encephalopathy with epileptic spasms. Magnetic resonance imaging of the brain showed bilateral hippocampal sclerosis in both, and one of them showed multiple cortical lesions with diffusion restriction. Two relevant missense variants in the GRIN1 gene were identified by a next-generation sequencing panel, one was novel (c.1927A > G-p.(Ile643Val)) and the other (c.2530C > T-p.(Arg844Cys)) was previously reported associated with GRIN1-neurodevelopmental disorder. Both variants are predicted to affect the normal function of the GluN1 subunit and were classified as likely pathogenic and pathogenic, respectively. Conclusion The association of severe cognitive impairment, autistic features with hand stereotypies, self-injurious behavior, and hyperkinetic movements in patients with epileptic encephalopathy are characteristic of GRIN1 encephalopathy. The hippocampal sclerosis and cortical lesions, similar to those found in NMDA autoimmune encephalitis, observed in these patients expand the neuroradiological features of this entity.