A pediatric patient with drug-resistant seizures and early-onset epileptic encephalopathy was found to have a recurrent variant of the missense glutamate ionotropic receptor NMDA type subunit 1 (GRIN1). These results 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 using Xenopus oocyte transfer.
At birth, the baby weighed 6 pounds 15 ounces, had Apgar scores of 8 and 9 after 1 and 5 minutes, respectively, and had no difficulty breathing or breastfeeding.
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For the first 10 weeks of life, the parents noticed that the baby suddenly stretched both arms for 1 to 2 seconds at least 10 times a day. After 12 weeks of life, episodes of head rotations to the right, accompanied by rapid lateral eye movements with arm extension and leg flexion, were observed several times a day. These episodes increased in frequency until the parents could no longer count.
The patient was on adrenocorticotropic hormone therapy (150 units / m2) at 3 months of age which showed a 50% reduction in the incidence of epileptic convulsions, but without complete resolution. Within 4 weeks the patient recovered to 30 to 50 daily spasms and no response to treatment with felbamate, clobazam or vigabatrin was achieved.
At 4 months of age, the patient was admitted to the hospital for long-term monitoring. Electroencephalogram identified infantile convulsions and tonic seizures. At 10 months of age, the patient developed tonic-clonic seizures. At 12 months the patient showed severe developmental retardation with hypotension and poor head control, appendicular hypertension, spasticity, and diffuse hyperreflexia.
Genetic analysis identified a missense variant that 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 previously observed in a 14-year-old boy who had severely delayed development and an onset of seizures at the age of 2 months.
In-vitro tests showed that the variant had a reduced magnesium blocking capacity compared to the wild type (inhibition capacity, 85% vs. 98%; P <0.05). Drugs targeting the N-methyl-D-aspartate receptor subunits of GRIN showed increased efficacy against the variant with significant responses to memantine, ketamine, dextromethorphan, and amantadine (all P <0.05).
At the age of 14 months, the patient received therapy of 0.2 mg / kg memantine daily, which was increased to 0.4 mg / kg / day in 2 weeks. 3 weeks later, the patient showed a reduced frequency of spasms (once every 2-3 weeks).
This study used genetic discovery and an in vitro approach to elucidate which approved therapies would be most effective at reducing seizures in a pediatric patient with a missense mutation in GRIN1. These results further the understanding of the genotype-phenotype relationship between genetics and seizure and demonstrate the potential success of precision medicine.
reference
Y. Xu, R. Song, W. Chen 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
