- Epilepsy is one of the most common neurological conditions, affecting one in 25 people.
- The severity of epilepsy varies among those living with the condition and can be influenced by genetics, brain function and environmental and personal factors.
- Experts from The Florey have contributed to international research that has uncovered new genetic insights that could lead to improved diagnosis and treatment of certain types of epilepsy.
Between 30-40 percent of people living with epilepsy have a family history of the disease, but the pattern of inheritance differs depending on the type of genetic mutation involved.
Previous research has found a link between epilepsy and GABRA3 receptor gene mutations (inherited through the X-chromosome), but the effect of the mutations on carriers has been unclear.
Now researchers from The Florey, the University of Sydney and the University of Southern Denmark have shown certain GABRA3 variants do cause epilepsy and developmental problems. Importantly, they discovered that the severity of disease among people with these gene mutations can vary dramatically.
The research, published in The Journal of Clinical Investigation, demonstrated that it is the functional impact of the gene variant, not its mere presence, that determines its effect on an individual.
To better understand the role of GABRA3 gene mutations, researchers studied 43 people with 19 different GABRA3 variants and found two distinct categories — those that worked too well (gain of function variants) and those that worked poorly (loss of function variants).
Gain-of-function variants were associated with severe, treatment-resistant epilepsy and profound intellectual disability, disproportionately affecting males.
Loss-of-function variants produced milder disease traits, with epilepsy rarely seen. Affected males displayed behavioral issues and language delay, while females were unaffected carriers.
Head of The Florey’s Epilepsy and Neurodevelopment Research Priority and co-author, Professor Christopher Reid, said the results were surprising because they dispelled a long-held assumption.
“The thinking was that all disease-causing GABRA3 variants were loss-of-function mutations. We now know that some variants instead increase receptor activity and are linked to much more severe epilepsy,” Professor Reid said.
“This is because the GABRA3 gene is found on GABAA receptors of the brain, which act as the brain’s brakes, preventing excessive neural activity.
“It was therefore surprising to discover that GABAA receptors that work better can cause epilepsy.”
Research Fellow, Dr Khaing Phyu Aung, led The Florey’s contribution to the research by using the first mouse model of gain-of-function GABRA3-associated epilepsy to support the team’s findings.
“These models are powerful tools for uncovering disease mechanisms and can also be used to test potential new therapies, bringing hope for improved treatments for individuals affected by this devastating condition,” Dr Aung said.
“Clarifying the role of GABRA3 mutations in epilepsy will allow for more informed genetic counselling, more targeted medicine and will also help more broadly to interpret X-linked neurodevelopmental disorders.”
