New disease gene for epilepsy and developmental disorder discovered

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 (Image: Pixabay CC0)
(Image: Pixabay CC0)

GABAA receptors play a central role in the development of epilepsy and developmental disorders, with nine out of 19 GABAA receptor genes already associated with genetic diseases. Now, as part of an international study led by Martin Krenn from MedUni Vienna’s Department of Neurology, GABRA4 has been identified as a new disease gene in four cases. The results of the research work were recently published in the prestigious "European Journal of Human Genetics".

An international collaboration has identified a total of four cases in Europe and the USA with the new neurogenetic disease, which is caused by de novo variants (spontaneous mutations) in the GABRA4 gene. The clinical symptoms of those affected are extremely variable and consist primarily of developmental delay, epileptic seizures, EEG abnormalities, attention deficits and autism spectrum disorder.

Thanks to close collaboration with the Centre for Physiology and Pharmacology (Ralph Gradisch, Thomas Stockner) and the Centre for Brain Research (Florian D. Vogel, Margot Ernst) of the MedUni Vienna, it was also possible to decipher the underlying molecular mechanisms and further substantiate the pathogenic relevance of the detected variants. "This work impressively demonstrates the high value of collaborations at an international level and emphasises the importance of close cooperations within our university in order to get to the bottom of neuroscientific issues. Nevertheless, we are only at the beginning of our understanding of this new disease and further cases and a detailed functional analysis of the mutations are required," emphasises corresponding author Martin Krenn.

Steps towards therapy

It has already been shown several times in the past that a detailed molecular understanding of genetic epilepsies is an essential prerequisite for the use of targeted therapies. This aspect appears particularly relevant in connection with GABAA receptors, as these are a known target for various anti-seizure medications.

Publication: European Journal of Human Genetics

De novo variants in GABRA4 are associated with a neurological phenotype including developmental delay, behavioral abnormalities and epilepsy.
Sajan SA*, Gradisch R*, Vogel FD, Coffey AJ, Salyakina D, Soler D, Jayakar P, Jayakar A, Bianconi SE, Cooper AH, Liu S, William N, Benkel-Herrenbrück I, Maiwald R, Heller C, Biskup S, Leiz S, Westphal DS, Wagner M, Clarke A, Stockner T, Ernst M, Kesari A, Krenn M#.
doi: 10.1038/s41431’024 -01600-3 .
*shared first authors
# last/corresponding author