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.

Keywords

epileptic encephalopathy - GRIN1 - molecular - NMDA receptor - neuroradiological features

Ethics Approval and Consent to Participate

This study was approved by the Institutional Ethics Committee of Hospital de Pediatría S.A.M.I.C. “Prof. Dr. Juan P. Garrahan. Written informed consent for the genetic studies was obtained from the parents of both patients.

Consent for Publication

Written informed consent was obtained from the parents of both patients for publication.

Authors' Contribution

M.L. and M.J. drafted the manuscript. A.G., M.E.M., G.R., G.V., C.R., C.A., and R.C. participated in the acquisition, analysis, and interpretation of data. C.A. and R.C. contributed to the conception of the study and substantively revised the manuscript. All authors read the final version of the manuscript and approved it for publication.

Availability of Data and Materials

ClinVar submission ID for genetic data are SCV002573458.1 and SCV002525850.1.

Publication History

Received: 17 January 2024

Accepted: 16 May 2024

Article published online:
13 June 2024

• References

• 1 Burnashev N, Szepetowski P. NMDA receptor subunit mutations in neurodevelopmental disorders. Curr Opin Pharmacol 2015; 20: 73-82
• 2 Traynelis SF, Wollmuth LP, McBain CJ. et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 2010; 62 (03) 405-496
• 3 Hansen KB, Wollmuth LP, Bowie D. et al. Structure, function, and pharmacology of glutamate receptor ion channels. Pharmacol Rev 2021; 73 (04) 298-487
• 4 Paoletti P. Molecular basis of NMDA receptor functional diversity. Eur J Neurosci 2011; 33 (08) 1351-1365
• 5 Xu Y, Song R, Chen W. et al. Recurrent seizure-related GRIN1 variant: molecular mechanism and targeted therapy. Ann Clin Transl Neurol 2021; 8 (07) 1480-1494
• 6 Lemke JR, Geider K, Helbig KL. et al. Delineating the GRIN1 phenotypic spectrum: a distinct genetic NMDA receptor encephalopathy. Neurology 2016; 86 (23) 2171-2178
• 7 Vanderver A, Simons C, Helman G. et al; Leukodystrophy Study Group. Whole exome sequencing in patients with white matter abnormalities. Ann Neurol 2016; 79 (06) 1031-1037
• 8 Ohba C, Shiina M, Tohyama J. et al. GRIN1 mutations cause encephalopathy with infantile-onset epilepsy, and hyperkinetic and stereotyped movement disorders. Epilepsia 2015; 56 (06) 841-848
• 9 Zehavi Y, Mandel H, Zehavi A. et al. De novo GRIN1 mutations: an emerging cause of severe early infantile encephalopathy. Eur J Med Genet 2017; 60 (06) 317-320
• 10 Santos-Gómez A, Miguez-Cabello F, Juliá-Palacios N. et al. Paradigmatic de novo grin1 variants recapitulate pathophysiological mechanisms underlying grin1-related disorder clinical spectrum. Int J Mol Sci 2021; 22 (23) 1-19
• 11 Fry AE, Fawcett KA, Zelnik N. et al. De novo mutations in GRIN1 cause extensive bilateral polymicrogyria. Brain 2018; 141 (03) 698-712
• 12 Scala M, Amadori E, Fusco L. et al. Abnormal circadian rhythm in patients with GRIN1-related developmental epileptic encephalopathy. Eur J Paediatr Neurol 2019; 23 (04) 657-661
• 13 García-Recio A, Santos-Gómez A, Soto D. et al. GRIN database: a unified and manually curated repertoire of GRIN variants. Hum Mutat 2021; 42 (01) 8-18
• 14 Wang J, Wen Y, Zhang Q. et al. Gene mutational analysis in a cohort of Chinese children with unexplained epilepsy: identification of a new KCND3 phenotype and novel genes causing Dravet syndrome. Seizure 2019; 66 (66) 26-30
• 15 Furuse T, Wada Y, Hattori K. et al. Phenotypic characterization of a new Grin1 mutant mouse generated by ENU mutagenesis. Eur J Neurosci 2010; 31 (07) 1281-1291
• 16 Krey I, Platzer K, Esterhuizen A. et al. Current practice in diagnostic genetic testing of the epilepsies. Epileptic Disord 2022; 24 (05) 765-786