What Is GRIN2A?
GRIN2A is a gene found on chromosome 16. It provides instructions for making a protein in the brain called glutamate ionotropic receptor that forms a subunit of the NMDA (N-methyl-D-aspartate) receptor (GluN2A).
The GluN2A protein is one of many types of proteins that make up glutamate receptors. In this case, it makes up NMDA receptors. These receptors present in the membranes of nerve cells (neurons) in the brain and spinal cord.
In normal brain development, these receptors are involved in the changes that happen in the brain because of a person's experiences, memory, and even sleep. GluN2A also determines where the receptor lives in the brain and how it will work.
Epilepsies Associated With GRIN2A Variants
GRIN2A variants are associated with epileptic encephalopathies such as Landau-Kleffner Syndrome (LKS) and Continuous Spike and Wave During Sleep (CSWS). They are also associated with other encephalopathic phenotypes.
GRIN2A variants have also been identified in people with focal epilepsies. An example includes childhood epilepsy with centrotemporal spikes (CECTS).
Seizure Types Associated With GRIN2A Variants
Some seizure types, such as focal seizures (aware and impaired aware) are the primary symptoms of GRIN2A-related epilepsy. Focal seizures are seen in more than half of individuals with GRIN2A-related epilepsy.
Generalized seizures may occur in up to 10% of cases. This includes:
Symptoms Seen With GRIN2A Variants
About one third of people with a GRIN2A variant have normal development and normal intellect. More than 90% of individuals have speech abnormalities. These include speech delay to language disorders, such as abnormal intonation or speech articulation errors.
Children with more severe types of GRIN2A-related disorders often have one or more of the following features:
- Developmental delay and intellectual disability
- Muscular hypotonia
- Attention deficit hyperactivity disorder (ADHD)
- Behavioral problems
- Sleep difficulties
How Is GRIN2A Diagnosed?
GRIN2A variants can only be identified by genetic testing. Targeted testing of the GRIN2A gene is done when there is a high degree of confidence that a variant in the GRIN2A gene is likely to be the underlying cause. However, epilepsy gene panels, which involve testing of multiple epilepsy-associated genes, and sequencing of genes also identify GRIN2A variants and are used more commonly than single gene tests.
Genetic counseling prior to genetic testing is an important step in making sure that the best testing strategy is selected, and that patients and families understand the risks, benefits, limitations and outcomes of testing.
How Is GRIN2A Treated?
Treatment is often targeted at the abnormal EEG activity that is seen during sleep (ESES). Medications commonly used for ESES include benzodiazepines and steroids. There is also some limited evidence in the literature for the use of a medication called memantine for treatment of seizures in individuals with GRIN2A variants.
Many other therapies have been reported to be helpful, including:
- Ketogenic diet
- Valproic acid
How Common Is GRIN2A-related Epilepsy?
Disclaimer: We do not have adequate data to be able to report with certainty how common GRIN2A-related epilepsy may be, though more than 500 variants in the GRIN gene family have been catalogued in the Center for Functional Evaluation of Rare Variants.
Variants in GRIN2A appear to be rare, but they are increasingly recognized and may be seen in up to 20% of children diagnosed with LKS/CSWS and 5% of those with CECTS.
What Is the Outlook for GRIN2A-related Epilepsy?
Disclaimer: This field is rapidly evolving, and everyone has their own course. We are constantly learning, and published data may be slow to come.
In some cases, epilepsy related to GRIN2A variants may be controlled with standard anti-seizure medications, while in other cases, seizures remain refractory despite medications.
Some individuals will continue to have difficult-to-control seizures in adulthood. ESES often resolves by puberty but may continue into adulthood.
Treatment is often directed at the ESES, because treatment may improve developmental and behavioral outcomes. Some individuals may have GRIN2A variants but not show any symptoms or have only mild symptoms without epilepsy.
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