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2023 ACMG Annual Clinical Genetics Meeting Digital ...
A Functionally Uncharacterized, Novel GRIA2 Varian ...
A Functionally Uncharacterized, Novel GRIA2 Variant: Advances in Targeted Epilepsy Management
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This article discusses the case of a 9-month-old male patient with a rare genetic variant in the GRIA2 gene, which encodes receptors that function as glutamate receptor subunits in the central nervous system. Variants in the GRIA2 gene can cause alterations in ion channels, leading to epilepsy and neurodevelopmental disorders.<br /><br />The patient initially presented with symptoms such as fussiness, stiffening, and exaggerated startle reflex. He experienced focal seizures and underwent multiple hospitalizations due to increasing seizure length and frequency. Genetic testing revealed a de novo variant in the GRIA2 gene, which had not been previously reported.<br /><br />The patient's seizures were not improving with multiple anti-epileptic drugs, so the medication perampanel was added to his treatment regimen. Perampanel is an antagonist of the glutamate receptors encoded by the GRIA2 gene and has been shown to be effective in blocking their currents. There had been one previous report of a patient with a confirmed gain-of-function variant in GRIA2 who saw a decrease in seizure burden with perampanel.<br /><br />However, it was unclear whether the patient's variant was a gain or loss-of-function variant at the time of medication initiation. To monitor for any adverse effects, the patient's medication dose was titrated slowly. As a result, the patient experienced a significant decrease in seizure burden, with multiple seizure-free weeks. He also showed improvements in sleep, feeding, and gross motor skills.<br /><br />This case highlights the potential benefit of perampanel for patients with GRIA2 variants and intractable epilepsy. In cases where the function of a novel genetic variant is unknown, it may not be practical to wait for variant modeling to determine its function. Instead, starting with low medication doses and closely monitoring patients can help improve their symptoms.
Asset Subtitle
Presenting Author - Reilly Philliben, DO;
Meta Tag
Biochemical genetics
Brain/Nervous System
Cognitive Disorders
Genome sequencing
Intellectual disability
Molecular Pathophysiology
Therapy
Presenting Author
Reilly Philliben, DO
Keywords
GRIA2 gene
glutamate receptor subunits
ion channels
epilepsy
neurodevelopmental disorders
focal seizures
perampanel
seizure burden
sleep
intractable epilepsy
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