By: Shree Rath
Gene Function:
The GRIN2A gene is situated on the short arm of chromosome 16. It encodes the GluN2A subunit of the N-methyl-D-aspartate (NMDA) receptor, a critical component in synaptic transmission within the central nervous system. The NMDA receptor, essential for learning and memory processes, relies on the precise functioning of the GluN2A subunit to maintain the delicate balance of excitatory neurotransmission. NMDA receptors are both ligand-gated and voltage-dependent and are involved in long-term potentiation, an activity-dependent increase in the efficiency of synaptic transmission thought to underlie certain kinds of memory and learning. These receptors are permeable to calcium ions, and activation results in a calcium influx into post-synaptic cells, which results in the activation of several signaling cascades.
Mutation:
Genetic mutations in GRIN2A can introduce disruptions in the function of the GluN2A protein, potentially leading to abnormal excitatory signaling. These mutations, ranging from missense to truncating variants, can act as genetic triggers for the onset of seizures and are implicated in various epilepsy syndromes.
Associated Epilepsy:
GRIN2A mutations have been associated with a spectrum of epilepsy syndromes. Seizure onset is typically between ages three and six years, although individuals may present from infancy to adolescence.
The most common seizure type overall is focal seizures. These are often associated with an aura of perioral paresthesia, and frequently evolve to generalized tonic-clonic convulsions. The predominant seizure type(s) in a given individual varies depending on which clinical syndrome is present.
The most common GRIN2A-related speech disorder and epilepsy is epilepsy-aphasia syndromes (EAS), a spectrum of disorders that includes:
Landau-Kleffner syndrome (LKS).
Epileptic encephalopathy with continuous spike-and-wave during sleep (ECSWS);
Childhood epilepsy with centrotemporal spikes (CECTS);
Atypical childhood epilepsy with centrotemporal spikes (ACECTS);
Autosomal dominant Rolandic epilepsy with speech dyspraxia (ADRESD).
Other epilepsy phenotypes can be broadly divided into infantile-onset epileptic encephalopathy and unclassified childhood epilepsy.
Signs and Symptoms:
Individuals with GRIN2A-associated epilepsy may present with a diverse array of seizure types and clinical manifestations.
Epilepsy aphasia syndrome, also known as Landau-Kleffner syndrome (LKS), is characterized by the gradual loss of language skills and, in some cases, epileptic seizures. Some common features include:
- Language Regression: Gradual or sudden loss of language abilities, including difficulty understanding and using language. Impairment in both expressive (spoken or written) and receptive (understanding) language skills.
- Seizures: Seizures may accompany language regression in some cases. Seizures are often focal in onset, originating from one area of the brain. They may evolve into more generalized seizures.
- Behavioral Changes: Changes in behavior, such as irritability, hyperactivity, or social withdrawal, may be observed.
- Sleep Disturbances: Sleep disturbances, including insomnia or altered sleep patterns, may occur.
- Abnormal EEG Patterns: Electroencephalogram (EEG) recordings often reveal abnormal patterns, especially during sleep. Continuous spike-and-wave discharges during sleep (CSWS) are characteristic EEG findings in LKS.
- Motor Skills: while the primary features center around language and seizures, some individuals may also exhibit changes in motor skills or coordination.
The age of onset is typically between 3 and 6 years, and the regression in language skills may occur gradually over weeks or months.
Other epilepsies, like Rolandic epilepsy present with seizures during sleep. The child may show facial twitching, drooling, and speech difficulties. The occurrence of seizures, especially during sleep, may disrupt normal sleep patterns and lead to daytime sleepiness.
Diagnosis:
A detailed medical history is crucial. This includes information about the onset and progression of symptoms, developmental milestones, and any family history of neurological or language disorders. LKS is characterized by a regression of language skills, particularly during sleep, and the emergence of seizures. Clinicians assess the nature and frequency of language regression, as well as the types of seizures present. Behavioral observations, both during wakefulness and sleep, can reveal specific language or cognitive impairments. EEG is a crucial tool in diagnosing LKS, to identify the characteristic continuous spike-wave discharges during slow-wave sleep (CSWS). Finally genetic tests can be conducted to identify GRIN2A gene mutations.
Treatment Modalities:
Early recognition and intervention can positively impact outcomes for individuals with LKS.
- Antiepileptic Medications: The selection of specific medications depends on the individual’s seizure type and response. Commonly used drugs include valproic acid, carbamazepine, and levetiracetam.
- Corticosteroids: Steroids like prednisone are usually administered in a short-term, high-dose regimen, aiming to normalize EEG abnormalities.
- Speech and Language Therapy: Speech and language therapy is a cornerstone in managing the language regression associated with LKS. Therapists work to improve communication skills, enhance vocabulary, and address any remaining language deficits.
- Sleep Management: Since LKS symptoms often worsen during sleep, establishing a consistent sleep schedule and ensuring a conducive sleep environment may contribute to symptom management.
- Monitoring and Regular Follow-up: Regular monitoring of seizure activity, EEG patterns, and overall progress is essential. Treatment plans may be adjusted based on the individual’s response and evolving needs.
References:
GRIN2A glutamate ionotropic receptor NMDA type subunit 2A [Homo sapiens (human)]. National Institute of Health, National Center for Biotechnology Information. Retrieved from: https://www.ncbi.nlm.nih.gov/gene/2903
Lemke, J. R., et al. (2013). GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction. Nature Genetics, 45(9), 1061–1066.
Myers KA, Scheffer IE. GRIN2A-Related Speech Disorders and Epilepsy. 2016 Sep 29. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK385627/#
Reutlinger, C., et al. (2019). De novo GRIN mutations in sporadic early-onset epileptic encephalopathies. Brain, 142(10), 3161–3178.
Swanger, S. A., et al. (2016). Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains. American Journal of Human Genetics, 99(6), 1261–1280.
