By: Sofia Arreguin
GABRA1 Related Epilepsy
What is GABRA1?
Gamma-aminobutyric acid, or GABA, is known to be an inhibitory neurotransmitter within the brain that often responds or binds to one of its subtypes, the GABAA receptor. This causes the formation of a hole, which the GABRA1 gene plays a significant role in producing, allowing the flow of chloride ions. This GABRA1 gene is responsible for supplying instructions for the formation of the alpha-1 subunit of the GABAA receptor (National Library of Medicine, 2012). This alpha-1 subunit then creates an opening within the cell membrane, where negatively charged ions, specifically chloride ions (Cl–), circulate, generating an environment that inhibits the communication, or signaling, between the cell’s neurons. This means that much excitatory activity within the brain is placated, which is crucial for those with epilepsy, who experience a high amount of excitatory activity, often as a result of high levels of glutamate, within the brain, resulting in seizures. However, variations, or mutations, in the GABRA1 gene can impact how a GABAA receptor responds to GABA, which may result in imbalances in neural activity, effectively reducing its ability to inhibit too much excitatory activity and, therefore, seizures (“GABRA1,” n.d.).
GABRA1 – Related Epilepsy
Missense mutations in the GABRA1 gene have been associated with certain epilepsies, such as juvenile myoclonic epilepsy (JME), which involves recurrent, uncontrollable muscle movements and often occurs during childhood or adolescence. Missense mutations are described as modifications made in a DNA building block, meaning one protein is replaced with another, resulting in a different protein sequence. The variation occurs at the site of an amino acid building block in the alpha-1 subunit, specifically at the 322nd position within a protein sequence, where the protein is replaced with the amino acid asparagine (National Library of Medicine, 2012). This GABRA1 gene mutation causes an abnormal alpha-1 subunit to form, which effectively reduces the receptor’s ability to regulate neuronal activity or prevent overstimulation between neurons, resulting in seizures (Galanopoulou, 2010). This variant is often expressed as A332D and results in defective GABAA receptors, indicating a decline in their effectiveness to calm heightened neuronal activity or seizures.
Mutations in the GABRA1 gene also result in Generalized Epilepsy with Febrile Seizures Plus (GEFS+), which is characterized as capturing a wide array of seizure-causing disorders (National Library of Medicine, 2012). Seizure-types within this spectrum include febrile seizures, which are seizures that manifest when one has a fever; febrile status epilepticus, described as prolonged seizures during a fever; generalized seizures, such as absence seizures, where a patient becomes unconscious, myoclonic seizures, which include muscle spasms, and tonic-clonic seizures, which affect the whole body with convulsions; atonic seizures, which is a sudden loss of muscle tone; and focal seizures, which occur in specific brain regions (“GABRA1,” n.d.). Individuals with GABRA1 gene mutations may also experience cognitive and developmental problems, learning disabilities, language delays, hypotonia, which negatively impacts motor skills and produces delays in the ability to sit or walk, electroencephalogram (EEG) abnormalities, which is the brain’s abnormal electrical activity, and Developmental and Epileptic Encephalopathy (DEE), neurogological disorders identified by impairments to one’s development and early-onset epilepsy.
Treatment
There are certain treatments that can be given or applied to individuals with GABRA1 mutations and the resulting seizures from such variants. For instance, one medication treatment that can help the de novo GABRA1 variant R214C is Verapamil (Bai et al., 2019). This variant is normally associated with epileptic encephalopathy (EE), in which one’s epilepsy or seizures often result in cognitive or behavioral disorders. The R214C mutation reduces the activity of GABAA receptors, resulting in a decline in the current, or amount of, chloride ions flowing into a cell and the affected neurons. Verapamil works to counteract this by fully restoring, or maintaining open, the gaps of such currents, allowing the ions to enter and produce an inhibitory environment to act against the overstimulation of some neurons (Bai et al., 2019). There is also one mediation, or research project, that aims to find a way to treat GABRA1 gene variants. Their idea is that enhancing the expression of the alpha-1 in those with a GABRA1 gene mutation would re-establish the inhibitory environment GABRA1 usually helps to produce and result in a decline of one’s epileptic symptoms, or inhibit seizures (Barberis, 2021). They would attempt to achieve this by using a technological tool called ‘SINEUP,’ in which they would be able to enhance the expression of a gene that they target, or choose; they have already detected SINEUPs that can enhance the alpha-1 protein. This would maintain the opening through which chloride ions flow.
While there is no cure or definitive treatment that would abolish this condition, there are treatments that could alleviate symptoms, such as seizure frequency and uncontrollable muscle spasms. It could be helpful to those with GABRA1 gene mutations to seek treatment, so that they could experience an improved quality of life.
References
Bai, Y. F., et al. (2019). Pathophysiology of and therapeutic options for a GABRA1 variant linked to epileptic encephalopathy. Molecular brain, 12(1), 92. https://doi.org/10.1186/s13041-019-0513-9
Barberis, A. (2021). RNA-Based Rescue of Inhibition as Potential Treatment for Genetic GABRA1-Dependent Epilepsy. Fondazione Telethon. https://www.fondazionetelethon.it/en/what-we-do/research/projects-funded/rna-based-rescue-of-inhibition-as-potential-treatment-for-genetic-gabra1-dependent-epilepsy-2/
“GABRA1.” (n.d.). Cure GABA A Variants. https://curegabaa.org/gabra1/
Galanopoulou A. S. (2010). Mutations affecting GABAergic signaling in seizures and epilepsy. Pflugers Archiv : European journal of physiology, 460(2), 505–523. https://doi.org/10.1007/s00424-010-0816-2
National Library of Medicine. (2012, June 1). GABRA1 Gene. MedlinePlus. https://medlineplus.gov/genetics/gene/gabra1/
