New Study Discovers Gene Associated with Epilepsy and Autism

A genetic mutation or variation in the SCN2A gene is known to cause infantile seizures, autism spectrum disorder, and intellectual disability, among other moderate-to-severe impairments in movement, communication, feeding, and vision.

The severity of these problems varies significantly from person to person, but little is understood about what is going on at the SCN2A protein level that causes these differences.

A new Northwestern Medicine research explains how alterations in the SCN2A gene influence whether or not a child develops autism or epilepsy, the age at which seizures begin for those with epilepsy, and the degree of the child’s other impairments.

The findings were published on April 24^th, 2024 in Brain, a leading neurology journal.

These discoveries will aid in better identifying individuals who are best suited for clinical trials of novel precision drugs, including those targeting the SCN2A gene itself.

Analyzing Sodium Channels

The FamilieSCN2A Foundation, a parent-led advocacy group for rare diseases, and a Northwestern academic laboratory collaborated on this study. To determine the SCN2A variations of 81 families from around the globe, the SCN2A Clinical Trials Readiness Study (SCN2A-CTRS) gathered comprehensive clinical data and metadata.

The age distribution was 5.4 years. 29 years old was the oldest participant's age, while the youngest was 1 month old.

The functional effects of each SCN2A variant on sodium channels, which are tiny gates in nerve cell membranes that regulate the flow of sodium ions into the cell and facilitate neurons in the brain to fire properly, were thoroughly examined by Northwestern study. Variations in the SCN2A gene change the function of the sodium channel.

The channel can be hyperactive (sodium ions flowing more easily) or entirely inert (the channel not operating at all), depending on the specific type. Variants enable the channel to function in more intricate ways.

The study discovered a range of impacts of SCN2A variants on sodium channel function, from hyperactive to entirely inert channels. Importantly, the child’s clinical condition varied according to the functional influence of the channel. Hyperactive channels were frequently linked to seizure onset in the first week of life.

When the age of seizure onset increased, so did the prevalence of reduced channel function. In fact, practically all individuals who did not experience seizures had entirely deactivated sodium channels.

Other disease-related parameters followed a similar gradient, with individuals with the most severe impairment (inability to walk, talk, eat, or use their hands), the youngest age at seizure start, and hyperactive channels. As the child’s age upon seizure initiation grew and channels were less active, serious neurological abnormalities decreased.

We previously knew that genetic changes in the SCN2A gene were associated with seizures beginning as early as the newborn period and up through the first few years of life. We had an overly simplistic understanding of these associations. Our new study clarifies the relationship between the functional consequences of SCN2A mutations, the primary phenotype (autism versus epilepsy and age at seizure onset in those with epilepsy) and the overall severity of the child’s impairments (mobility, etc.)."

Dr Alfred George, Study Co-Corresponding Author and Chair, Department of Pharmacology, Northwestern University

Findings Challenge Prevalent Understanding

According to George, researchers generally believe that early-onset seizures are caused by hyperactive sodium channels, whereas underactive or inactive channels are associated with autism. However, it is more difficult, and children with early onset (in the first three months but beyond the neonatal period) do not have hyperactive channels.

George added, “This is important because new precision medicines that are best suited for hyperactive SCN2A variants could be harmful to those with underactive or inactive variants.”

Dr Anne Berg, Adjunct Professor of Neurology at Feinberg, lead investigator of the SCN2A-CTRS and the co-corresponding study author emphasized that “in the era of precision medicine for rare genetic diseases, this collaboration between a family foundation and a large NIH-funded project is an exemplar of the new partnerships that are needed and increasingly being developed to provide rapid answers to critical questions and lay foundation for successful drug development for severe neurodevelopmental disorders such as those associated with SCN2A.”

The CTRS was driven by patient community stakeholders and exemplifies the kind of efforts recommended by the new US Food and Drug Administration Patient-Focused Drug Development Guidance initiative, which was created in response to a mandate from the 21^st Century Cures Act, Berg stated.