The GRIN2A gene provides instructions for making a specific protein that plays a role in brain function. This gene is located on the short arm of chromosome 16. The protein produced by GRIN2A is considered fundamental for proper brain activity.
What GRIN2A Does in the Brain
The GRIN2A gene provides the blueprint for a protein called GluN2A, also known as NR2A. This protein is a component, or subunit, of the N-methyl-D-aspartate (NMDA) receptor. NMDA receptors are a type of ion channel found in nerve cells throughout the brain and spinal cord, including areas involved in speech and language.
NMDA receptors are glutamate-gated ion channels. When the channel opens, positively charged particles, called cations, flow into the neuron. This generates electrical currents that activate neurons, allowing them to send signals within the brain. NMDA receptors are involved in normal brain development, synaptic plasticity (the brain’s ability to change in response to experience), learning, and memory. The GluN2A subunit specifically influences where in the brain the NMDA receptor is located and how it functions.
Conditions Linked to GRIN2A Mutations
Mutations in the GRIN2A gene can lead to a range of neurodevelopmental disorders. These genetic changes disrupt the normal function of the GluN2A protein, leading to abnormal signaling within the brain.
A common manifestation of GRIN2A mutations is epilepsy, present in over 85% of affected children. Seizure onset typically occurs between ages three and six years, though it can range from infancy to adolescence. The epilepsy-aphasia spectrum disorders, which include Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS), are frequently linked to GRIN2A mutations. LKS is characterized by a gradual loss of language skills, sometimes accompanied by seizures, while ECSWS involves abnormal electrical activity in the brain during sleep. Other common seizure types include focal seizures, which may involve tingling around the mouth and can progress to generalized tonic-clonic convulsions.
Beyond epilepsy, GRIN2A-related conditions often involve developmental delays and intellectual disability. Speech and language disorders are particularly common, affecting over 90% of individuals. These can include difficulties coordinating speech sounds (dysarthria or speech apraxia), delays or regression in language development, and issues with conversational speech.
Movement disorders, such as ataxia (lack of coordination), dystonia (involuntary muscle contractions), or chorea (jerky, involuntary movements), occur less frequently. Additionally, some individuals may experience decreased muscle tone (hypotonia) and behavioral issues, including features of autism spectrum disorder or attention-deficit/hyperactivity disorder.
Identifying and Managing GRIN2A-Related Conditions
Diagnosing GRIN2A-related conditions primarily relies on genetic testing. While certain clinical features, such as speech and language disorders combined with early childhood seizures, might suggest a GRIN2A-related disorder, a definitive diagnosis requires identifying a pathogenic variant in the GRIN2A gene. Genetic tests like whole exome sequencing or gene panels, which analyze multiple epilepsy-associated genes, are commonly used to identify these mutations. Additional diagnostic tests may include an electroencephalogram (EEG) to detect abnormal brain activity and seizures, and magnetic resonance imaging (MRI) to assess for changes in brain structure.
Management of GRIN2A-related conditions focuses on addressing the symptoms and improving functional abilities. Anti-epileptic medications are a primary treatment for controlling seizures, and a combination of these medications may be used depending on the seizure types. For some individuals, targeted therapies, such as treatment with the N-methyl-D-aspartate receptor coagonist L-serine, have shown improvements in behavior, development, and seizure frequency, particularly in those with specific types of GRIN2A variants. However, certain medications and activators of the NMDA receptor should be avoided in individuals with gain-of-function variants, as they could worsen symptoms.
Supportive care involves a multidisciplinary team approach. Speech-language pathologists are involved to address significant speech and language deficits. Physical and occupational therapies are often recommended to manage developmental delays, improve muscle tone, and enhance motor skills. A developmental pediatrician can oversee the overall care, monitoring development and behavior, and guiding the best forms of help. In some cases, implantable devices like vagus nerve stimulation (VNS) or responsive neurostimulation (RNS) may be considered if medications are not effective in controlling seizures.