Targeted Therapy for Recurrent Seizure-Related GRIN1 Variant

A recurrent missense glutamate ionotropic receptor NMDA type subunit 1 (GRIN1) variant was found to be carried by a pediatric patient with drug-resistant seizures and early-onset epileptic encephalopathy. These findings were published in the Annals of Clinical and Translational Neurology.

A boy aged 24 months underwent whole exome sequencing. Electrophysiological recordings and drug response assays were performed via Xenopus oocyte transfer.

At birth, the baby weighted 6 pounds 15 ounces, had Apgar scores of 8 and 9 at 1 and 5 minutes, respectively, and did not exhibit difficulty breathing or breastfeeding.

During the first 10 weeks of life, the parents noticed the baby would extend both arms suddenly for 1 to 2 seconds at least 10 times daily. At 12 weeks of life, episodes of head turning to the right accompanied by rapid side-to-side eye movements with arm extension and leg flexion were observed multiple times per day. These episodes increased in frequency to the point in which the parents could not keep count.

The patient was given adrenocorticotropic hormone therapy (150 units/m²) at 3 months of age, for which he had a 50% frequency reduction in epileptic spasms, but without complete resolution. Within 4 weeks, the patient rebounded to 30 to 50 spasms daily and no treatment response was achieved by felbamate, clobazam, or vigabatrin.

At 4 months of age, the patient was admitted to the hospital for long-term monitoring. Electroencephalogram identified infantile spasms and tonic seizures. After 10 months of age, the patient developed tonic-clonic seizures. At 12 months, the patient exhibited a severe delay in development with hypotonia and poor head control, appendicular hypertonia, spasticity, and diffuse hyperreflexia.

Genetic analysis identified a missense variant which caused a methionine to isoleucine substitution at amino acid site 641. This position is in the M3 transmembrane helix of the GluN1 subunit. The same variant was observed previously in a 14-year-old boy who had severely delayed development and seizure onset at 2 months of age.

In vitro assays found the variant had reduced magnesium block capacity (inhibition capacity, 85% vs 98%; P <.05) compared with wild type. Drugs which target the N-methyl-D-aspartate receptor subunits of GRIN showed enhanced potency against the variant, with significant responses to memantine, ketamine, dextromethorphan, and amantadine (all P <.05).

At 14 months of age, the patient was given a therapy of 0.2 mg/kg daily memantine which was increased to 0.4 mg/kg/day by 2 weeks. 3 weeks after this, the patient exhibited reduced frequency of spasms (once every 2-3 weeks).

This study used a genetic discovery and in vitro approach elucidate which approved therapies would be most effective at reducing seizures for a pediatric patient carrying a missense mutation in GRIN1. These findings further the understanding of the genotype-phenotype relationship between genetics and seizure and demonstrate the potential success of precision medicine.

Reference

Xu Y, Song R, Chen W, et al. Recurrent seizure-related GRIN1 variant: Molecular mechanism and targeted therapy. Ann Clin Transl Neurol. Published online July 6, 2021. doi:10.1002/acn3.51406