GRIN2A

More than 50 mutations in the GRIN2A gene have been identified in some people with conditions that fall along the epilepsy-aphasia spectrum. This group of conditions is characterized by abnormal electrical activity in the brain, usually during slow-wave sleep; a loss of speech and language skills and sometimes other developmental skills; and in many cases, recurrent seizures (epilepsy). Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS) are at the severe end of the spectrum, while childhood epilepsy with centrotemporal spikes (CECTS) is at the mild end. Several other conditions have signs and symptoms of intermediate severity.

Many GRIN2A gene mutations lead to production of a nonfunctional GluN2A protein or prevent the production of any protein at all. These mutations likely lead to a reduced number of NMDA receptors containing the GluN2A subunit. Researchers suspect that, as a result, signaling occurs through other types of NMDA receptors that more easily excite neurons, leading to excessive signaling in the brain. Other mutations lead to production of abnormal GluN2A proteins that likely alter how the NMDA receptors function, possibly increasing signaling. Excessive activity of neurons in the brain can lead to seizures and other abnormal brain activity and may result in death of the neurons. 

Changes in GluN2A appear to specifically affect signaling in regions of the brain involved in speech and language and disrupt brain activity during slow-wave sleep, leading to several of the signs and symptoms of this group of conditions. It is not clear why some GRIN2A gene mutations lead to a relatively mild condition and others cause more severe signs and symptoms.

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GRIN2A gene mutations have been found in people with neurological disorders that have features similar to epilepsy-aphasia spectrum disorders (described above) but lacking consistent language problems. These shared features can include recurrent seizures (epilepsy), often of a type that originates from abnormal activity in the rolandic region of the brain (rolandic epilepsy); intellectual disability; and developmental delay. Some people with mutations in chromosome 16 that delete the GRIN2A gene as well as other nearby genes also have unusual facial features. The varying effects of different GRIN2A gene mutations and how they contribute to different neurological disorders are under study.