HMN 2026: How MDGA2 gene malfunction removes brain’s excitatory ‘brake’ to trigger severe epilepsy

The DGIST Center for Synapse Diversity and Specificity has identified MDGA2 as a novel causative gene for developmental and epileptic encephalopathy (DEE), a rare and intractable neurological disorder occurring in infancy and early childhood. This study advances the understanding of the causes of DEE and highlights the potential for early diagnosis and the development of new therapies.

DEE is a serious neurological disorder in which genetic abnormalities cause defects in brain development, leading to uncontrolled seizures beginning at a young age, accompanied by severe developmental delays. Although several causative genes have been identified to date, many patients still cannot have the precise cause of their condition determined, making treatment and genetic counseling challenging.

In collaboration with an international research team, Professor Jaewon Ko’s research team analyzed the genomes of eight patients from six families originating in the Middle East and Southeast Asia and identified loss-of-function variants in the MDGA2 gene as the cause of the disorder. The research is published in The American Journal of Human Genetics.

The patients commonly exhibited severe developmental delays, early-onset intractable seizures, and progressive brain atrophy. In some cases, the disease course was so severe that death occurred during infancy and early childhood.

The MDGA2 protein functions as a “brake” that prevents the excessive formation of excitatory synapses in the brain. However, this brake is lost when there is a genetic abnormality, causing neurons to become hyperexcitable and disrupting the balance of neural circuits.

This results in severe seizures and neurodevelopmental impairments in patients. This mechanism is analogous to a car speeding out of control due to brake failure.

This research is significant not only because it expanded the known genetic causes of DEE, but also because it elucidated the specific mechanisms underlying disease development.

In particular, it highlighted the potential for new therapeutic strategies that modulate MDGA2 function or reduce excessive excitatory signaling in the brain. In fact, partial seizure control was observed in some patients through a “ketogenic diet,” which restricts carbohydrates and emphasizes fat intake.

“This research has paved the way to accurate diagnosis for patients and families who had previously suffered without knowing the cause,” stated Professor Jaewon Ko. “Moving forward, we will pursue follow-up research aimed at developing fundamental therapies targeting MDGA2.”

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