The epilepsy-aphasia spectrum is a group of conditions that have overlapping signs and symptoms. A key feature of these conditions is impairment of language skills (aphasia). The language problems can affect speaking, reading, and writing. Another feature of epilepsy-aphasia spectrum disorders is certain patterns of abnormal electrical activity in the brain, which are detected by a test called an electroencephalogram (EEG). Many people with conditions in this spectrum develop recurrent seizures (epilepsy), and some have mild to severe intellectual disability. The conditions in the epilepsy-aphasia spectrum, which all begin in childhood, include Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep syndrome (ECSWS), autosomal dominant rolandic epilepsy with speech dyspraxia (ADRESD), intermediate epilepsy-aphasia disorder (IEAD), atypical childhood epilepsy with centrotemporal spikes (ACECTS), and childhood epilepsy with centrotemporal spikes (CECTS).

LKS and ECSWS are at the severe end of the spectrum. Both usually feature a characteristic abnormal pattern of electrical activity in the brain called continuous spike and waves during slow-wave sleep (CSWS). This pattern occurs while the affected child is sleeping, specifically during deep (slow-wave) sleep.

Most children with LKS develop normally in early childhood, although some speak later than their peers. However, affected children lose language skills beginning around age 5. This loss typically begins with verbal agnosia, which is the inability to understand speech. As LKS develops, the ability to express speech is also impaired. Approximately 70 percent of children with LKS have seizures, typically of a type described as focal (or partial) because the seizure activity occurs in specific regions of the brain rather than affecting the entire brain.

About half of children with ECSWS develop normally in early childhood, while others have delayed development of speech and motor skills. Although children with ECSWS typically lose a range of previously acquired skills, including those involved in language, movement, learning, or behavior, not everyone with ECSWS has aphasia. Seizures occur in approximately 80 percent of children with ECSWS and can include a variety of types, such as atypical absence seizures, which involve short periods of staring blankly; hemiclonic seizures, which cause rhythmic jerking of one side of the body; or generalized tonic-clonic seizures, which cause stiffening and rhythmic jerking of the entire body.

CECTS is at the mild end of the epilepsy-aphasia spectrum. Affected children have rolandic seizures; these seizures are triggered by abnormal activity in an area of the brain called the rolandic region, which is part of the cerebrum. The seizures, which usually occur during sleep, cause twitching, numbness, or tingling of the face or tongue, often causing drooling and impairing speech. In most people with CECTS, the seizures disappear by the end of adolescence. Most affected individuals develop normally, although some have difficulty coordinating the movements of the mouth and tongue needed for clear speech (dyspraxia) or impairment of language skills.

The other conditions in the epilepsy-aphasia spectrum are less common and fall in the middle of the spectrum. Children with IEAD usually have delayed development or regression of language skills. Some have seizures and most have abnormal electrical activity in their brains during sleep, although it is not prominent enough to be classified as CSWS. ACECTS features seizures and developmental regression that can affect movement, language, and attention. Children with ACECTS have abnormal electrical activity in the brain that is sometimes classified as CSWS. ADRESD is characterized by focal seizures, speech difficulties due to dyspraxia, and learning disability.

The prevalence of the epilepsy-aphasia spectrum is unknown. Most of the conditions in the spectrum are rare; however, CECTS is one of the most common forms of epilepsy in children, accounting for 8 to 25 percent of cases. It is estimated to occur in 1 in 5,000 children younger than 16.

Variants (also known as mutations) in the GRIN2A gene can cause conditions in the epilepsy-aphasia spectrum. These variants are more common in the more severe conditions; they are found in up to 20 percent of people with LKS or ECSWS and about 5 percent of people with CECTS. In affected people without a GRIN2A gene variant, the cause of the condition is unknown. Some affected individuals have a brain abnormality that may contribute to the condition. Researchers suspect that changes in other, unidentified genes may also be associated with epilepsy-aphasia spectrum disorders.

The GRIN2A gene provides instructions for making the GluN2A protein, which is one component (subunit) of a subset of NMDA receptors. NMDA receptors transmit signals that turn on nerve cells (neurons) in the brain. Signaling through these receptors is involved in normal brain development, changes in the brain in response to experience (synaptic plasticity), learning, and memory. The GluN2A subunit determines where in the brain the receptor is located and how it functions. Receptors containing this subunit are found in regions of the brain involved in speech and language, among other regions. These receptors also appear to play a role in brain signaling during slow-wave sleep.

Variants in the GRIN2A gene lead to altered NMDA receptor signaling in the brain. As a result, neurons may be abnormally turned on, which can cause seizures and other abnormal brain activity and may lead to death of the neurons. Changes in GluN2A appear to particularly 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 people with a GRIN2A gene variant have a relatively mild condition and others have more severe signs and symptoms, even within the same family. Variations in other genes and environmental factors may also play a role in development of the condition.

Normal Function

The GRIN2A gene provides instructions for making a protein called GluN2A (formerly known as NR2A). This protein is found in nerve cells (neurons) in the brain and spinal cord, including regions of the brain involved in speech and language.

The GluN2A protein is one component (subunit) of a subset of NMDA receptors. There are several types of NMDA receptors, made up of different combinations of protein components. NMDA receptors are glutamate-gated ion channels; when brain chemicals called glutamate and glycine attach to the receptor, a channel opens, allowing positively charged particles (cations) to flow through. The flow of cations generates currents that activate (excite) neurons to send signals in the brain. NMDA receptors are involved in normal brain development, changes in the brain in response to experience (synaptic plasticity), learning, and memory. They also appear to play a role during deep (slow-wave) sleep.

The GluN2A subunit of NMDA receptors determines where in the brain the receptor is located and how it functions. It also provides the site to which glutamate binds.

Health Conditions Related to Genetic Changes

Epilepsy-aphasia spectrum

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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Other disorders

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.

Other Names for This Gene

• EPND
• GluN2A
• glutamate receptor ionotropic, NMDA 2A isoform 1 precursor
• glutamate receptor ionotropic, NMDA 2A isoform 2 precursor
• glutamate receptor, ionotropic, N-methyl D-aspartate 2A
• LKS
• N-methyl D-aspartate receptor subtype 2A
• N-methyl-D-aspartate receptor channel, subunit epsilon-1
• N-methyl-D-aspartate receptor subunit 2A
• NMDAR2A
• NR2A

Genomic Location

Conditions in the epilepsy-aphasia spectrum that are caused by GRIN2A gene variants are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Individuals with an epilepsy-aphasia spectrum disorder may have family members with a condition in the epilepsy-aphasia spectrum or a related disorder such as isolated seizures or speech and language problems.

In some cases, an affected person inherits the variant from one affected parent. Other cases result from new variants in the gene and occur in people with no history of the disorder in their family.