A genetic link to the development of epilepsy and autism

Autism and epilepsy often coexist in a complex web of neurodevelopmental challenges. Seizures, a common symptom in both conditions, can significantly impact a child’s well-being and development. Pinpointing the exact cause of these disorders remains a challenging task due to their diverse nature and overlapping symptoms. 

Now, a Northwestern University research team led by pharmacologist Alfred George Jr. linked specific mutations in the SCN2A  gene, which encodes a sodium channel in the brain, to the development of epileptic seizures or autism without seizures in young children (1). Their new classification system for SCN2A  mutations established a direct link between the variant and disease severity, which could allow for more precise diagnosis and treatment of these diverse conditions.  

“The goal of the study was to define with a more expanded definition of the clinical phenotype,” said George Jr. 

SCN2A mutations disrupt voltage-gated sodium channels (Na_V1.2), which are crucial for neuron function. When an excitatory signal triggers membrane depolarization, Na_V1.2 changes conformation, rapidly opening the channel pore, and allows sodium to rush into the cell. When this function is impaired, neurons can’t communicate properly, potentially leading to developmental disorders like epilepsy.

George Jr. and his team previously investigated 32 SCN2A variants linked to early- and late-onset epilepsy (2). They found that the channel's function can vary widely depending on the specific variant. Some variants may allow sodium ions to flow more freely, leading to hyperactivity, while others may completely prevent the channel from working. Additionally, there are variants that can cause more intricate patterns of channel activity. So, George Jr. and his group decided to take a closer look at how these variants affected the severity of a child's illness.

George Jr. and his team collaborated with the SCN2A Clinical Trials Readiness Study (CTRS), led by neuroscientist Anne Berg, also at Northwestern University, who advocates for research on SCN2A-related disorders through the FamilieSCN2A Foundation. Through the CTRS, the researchers recruited 81 children from around the world with pathogenic variants of SCN2A. They grouped them based on the timing of their epilepsy diagnosis (neonatal: less than one month old, infant: between one and 11 months, or late: older than 12 months) and seizure severity (none, mild, or severe). They used cluster analysis, a data mining method, to group patients based on these variables and to determine genotype-phenotype relationships.

The researchers found that SCN2A variants directly correlated with the severity of the child's clinical condition. Children whose variants led to overactive SCN2A channels generally experienced seizures in the neonatal period, specifically in their first week of life. If the variants led to impaired channel function, those children experienced seizures later, during the infant and late periods. Finally, the kids with complete loss of SCN2A channel function typically had a much older age of seizure onset or fell into the autism with no seizures group. 

The hope is that those genetic tests are going to direct therapy much quicker in the life of a child than they have been [done] historically. 
- Alfred George Jr., Northwestern University

Peter Penzes, a neuroscientist at Northwestern University who was not involved in the study, said, "This was actually, to my knowledge, one of the most comprehensive studies where they correlated these molecular studies by recording currents, and also very thorough phenotyping of these patients.”

George Jr. and his group are now testing how different drugs interact with various SCN2A variants. In his future work, he hopes to collaborate with pharmaceutical companies to study patient-specific variants in other neurodevelopmental disorders.

“The hope is that those genetic tests are going to direct therapy much quicker in the life of a child than they have been [done] historically,” George Jr. said. “Rare disease therapeutics are hard to come by, and for those few bold companies that are pushing ahead with clinical trials, we wanted to get it right.”

Correction: This article was updated on September 17, 2024 to correct Peter Penzes' affiliation. He is a neuroscientist at Northwestern University. He is not employed by the Brain and Behavior Research Foundation.

References

1. Berg, A.T. et al. Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders. Brain  147, 2761-2774 (2024). 
2. Thompson, C.H. et al. Epilepsy-associated SCN2A (Na_V1.2) variants exhibit diverse and complex functional properties. J Gen Physiol  155, e202313375 (2023).