Paradoxical finding challenges understanding of genetically determined epilepsy

Breaking new ground 19. jun 2022 3 min Professor Rikke Steensbjerre Møller Written by Kristian Sjøgren

Research on a receptor in the brain has changed the understanding of epilepsy. This knowledge may lead to new types of treatment and more personalised drugs, says researcher.

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Researchers have made a remarkable discovery that changes the understanding of the mechanisms behind certain types of genetically determined epilepsy.

Researchers and doctors previously presumed that some forms of genetically determined epilepsy result from decreased function of the GABAA receptor, leading to reduced neuronal GABAergic activity in the brain. GABAA receptors respond to the major inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and are extremely important for maintaining healthy brain activity.

However, new research has shown that some types of genetically determined epilepsy actually result from increased function of GABAA receptors.

This major discovery provides new insight into how variants in genes coding for the GABAA receptor can lead to epilepsy through various mechanisms and paves the way for developing new types of treatment.

“This study found potential for developing new types of treatment for some people with epilepsy aimed at inhibiting an overactive GABAA receptor,” explains a researcher behind the study, Rikke Steensbjerre Møller, Professor, Danish Epilepsy Centre, Filadelfia and Department of Regional Health, University of Southern Denmark, Odense.

The study was carried out by researchers from the Danish Epilepsy Centre, Filadelfia and the University of Sydney, Australia, and the results have been published in Nature Communications.

Intricately balanced

The electrical activity in the human brain is intricately balanced. A decrease in this electrical activity causes a sedative effect and can lead to coma in the worst case. Conversely, when the electrical activity is overactive, epilepsy often results.

The inhibitory neurotransmitter GABA and the GABAA receptor, which together form the GABA system, play a crucial role in regulating the brain’s electrical activity.

GABA is released in all areas of the brain to fine-tune the signals transmitted around the body, and the key role of GABA is to inhibit neuronal activity. For example, if a brain cell becomes overactive, GABA’s inhibitory activity can counteract this overactivity by bringing it back to the normal state. GABA can also increase activity in an area of the brain by attenuating the activity of an inhibitory brain cell.

The current understanding is that mutations in the genes coding for the GABAA receptor cause the receptor to lose its ability to inhibit brain activity. And when this occurs, the electrical activity of the brain becomes overactive, resulting in epilepsy.

“It has always been thought that people with epilepsy could be treated with drugs that increase the activity of GABA to help to inhibit the brain’s electrical activity. Our study indicates that this does not apply to every case,” says Rikke S. Møller.

Rare variant leads to epilepsy

The researchers studied variants of GABRB3, a gene that codes for a GABAA receptor subunit, among people with epilepsy.

GABRB3 variants are very rare, and the researchers therefore had to collect people with these variants from all over the world.

The researchers investigated all GABRB3 variants and discovered that about half of these variants enhanced GABAergic activity (gain-of-function variants), and the other half were loss-of-function variants.

In addition to the genetic and functional studies, the people with epilepsy were categorised according to their illness trajectory.

  • Some had febrile seizures in early childhood and then developed generalised epilepsy that was easy to treat. They may also have mild intellectual disability.
  • Others developed epilepsy in the first months of life and were virtually impossible to treat. Many in this group could not sit, walk or stand. They were also very seriously ill and had severe intellectual disability.

Discovery surprised the researchers

To their great surprise, the researchers found that the people with an overactivated GABAA receptor were the group with very severe epilepsy.

This was the opposite of what they had expected, because epilepsy was believed to arise as a result of decreased GABAergic activity, leading to excessive excitation in the brain circuitry.

According to Philip K. Ahring, Associate Professor from the University of Sydney, another researcher behind the study, the results also indicate why some of the drugs used to treat people with epilepsy aggravate the symptoms of one group of patients by increasing the activity of an already excessively excited GABAA receptor.

“We have previously had great difficulty explaining why some people with variants of the gene affecting this receptor have had mild epilepsy, whereas others have become very severely ill. We can now see how these factors are connected and why this is important for how different types of drugs work,” explains Philip K. Ahring.

Discovery influences the choice of treatment

The new discovery has several implications.

The researchers behind the discovery have created a flow chart that enables doctors to easily determine whether people have gain-of-function or loss-of-function variants for the gene coding for the GABAA receptor.

Rikke S. Møller explains that the flow chart uses clinical features, including age of onset, severity of intellectual disability, decreased muscle tone and microcephaly (a smaller infant brain).

The epilepsy of anyone with these symptoms probably resulted from an excessively excited GABAA receptor.

“This influences the treatment a doctor chooses, and thus we are moving towards more personalised medicine for people with epilepsy,” says Rikke S. Møller.

Improving insight into epilepsy

Another perspective of the new study is identifying the need for developing new types of anti-epileptic medications that inhibit GABAergic activity instead of enhancing it.

Finally, the study suggests a new understanding of epilepsy as not always resulting from the loss of function of the GABAA receptor but sometimes a gain of function.

“We should now seek to understand why people become so seriously ill when the GABAA receptor is excessively excited. This will be our focus area, and an obvious hypothesis could be that brain damage may occur when the GABAA receptor is excessively excited during fetal development and that this manifests itself as epilepsy. Understanding the role of GABA in the development of epilepsy has become more nuanced with this study. We have always just considered loss of function in the GABAA receptor as causing epilepsy, but now we will also consider excessive inhibitory activity of the GABAA receptor,” concludes Rikke S. Møller.

Rikke Steensbjerre Møller is professor of epilepsy genetics at Department of Regional Health Research at University of Southern Denmark, and head of D...

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