Grin1-Related Early Onset Encephalopathy: A Distinct NMDA Receptor Dysfunction

Introduction: Pathogenic variants in GRIN1, which encodes the GluN1 subunit of the N-methyl-D-aspartate receptor receptor, have been identified in patients with nonsyndromic intellectual disability but also in early onset epileptic encephalopathy. We describe the phenotypic spectrum of three patients with de novo mutations in GRIN1, all diagnosed by next-generation sequencing analysis (clinical exome) highlighting some clinical features to suspect the disorder.

Case Reports: Case 1: Baby girl who presented with episodes of four limbs hypertonia and abnormal ocular movements since 30 hours of life together with hypokinesia and dystonic postures. At 3 months, onset of infantile spasms and tonic seizures refractory to antiepileptic drugs. At 9 months, no eye tracking nor visual attention, axial hypotonia without head control, limbs spasticity, and superior eye gaze deviation resembling oculogyric crisis. She deceased at 10 month in the context of respiratory insufficiency.

Case 2: Twenty months baby girl with severe development delay, axial hypotonia, no visual contact/attention, hyperkinetic movements, and epilepsy onset at 5 months with good seizure control with valproic acid. Episodes of superior eye gaze deviation resembling oculogyric crisis that improved with age.

Case 3: Nineteen years old girl with severe intellectual disability, axial hipotonia and four limbs spasticity, refractory epilepsy since 12 months of age, stereotyped movements, and autism spectrum disorder with severe behavior problems.

Video electroencephalography multifocal paroxysmal activity with slow background activity. Brain magnetic resonance imaging: asymmetrical ventriculomegaly (case 1) and cortical atrophy. Metabolic screening including neurotensin in cerebrospinal fluid: normal. A three different de novo missense variants in GRIN1 were found in a highly conserved domain of the protein and the bioinformatics predictive effect of the variants were deleterious. Functional analysis is in process.

Conclusions: Although a comprehensive phenotypic spectrum of GRIN1 pathogenic variants remains to be determined, key features of the disorder seem to be infantile-onset seizures with hyperkinetic and stereotyped movements, no visual contact and occasional abnormal eye movements resembling oculogyric crisis.