A New Gene in Hemiplegic Migraine

A recent study links variants in SCN2A, which encodes a sodium channel recognized for its role in epilepsy and autism, to familial and sporadic HM. Electrophysiology experiments and computational neuron models reveal multifaceted effects of the variants on cell excitability.

Familial hemiplegic migraine (FHM) is a rare migraine subtype for which researchers have identified just a handful of genes with a causal role. But since these known genes account for only a small proportion of genetically diagnosed cases, there is an ongoing search for additional genetic contributors. Now, new research adds to the genetic landscape of FHM by identifying novel genetic variants – with complex effects on cell electrical activity – associated with the condition.

The study, led by Anne Ducros, Hôpital Gui de Chauliac, Montpellier, France, and Alfred George, Jr., Northwestern University Feinberg School of Medicine, Chicago, US, reports new variants in SCN2A, a gene that makes a sodium channel, that are associated with FHM or sporadic HM (defined as a case with no known family history of HM).

The three variants pinpointed in the study caused a number of electrophysiological abnormalities affecting the electrical activity of cells. Further, computer simulations of neuronal action potentials indicated that the net effect of the SCN2A variants was an increase in electrical excitability.

“With the study, the SCN2A gene has now joined the ranks of genes that cause hemiplegic migraine,” said Ingo Helbig, Children’s Hospital of Philadelphia, US, a clinical neurogeneticist who studies HM but was not involved with the new work.

“Hemiplegic migraine is such an unusual presentation that we don’t even have a full grasp on where these families are and how many families [are affected],” he continued. “So this is why I think, as a field, it’s very rewarding to see that there’s another cause that we can now add to the list of genes.”

The study appeared online ahead of print on March 26, 2026, in the journal Brain.

“A little serendipity”
The new work was a collaboration between Ducros, a headache specialist and researcher who led the genetic mapping part of the study, and George, who studies the functional consequences of ion channel mutations and led that part of the research. A chance encounter – both investigators were attending the same meeting – led to the collaborative study.

“We didn’t know each other, but she had mentioned to a colleague that [she and her collaborators] had done a genetic study on families that had FHM but did not have any of the known genes,” George told Migraine Science Collaborative in an interview. “They had come upon a convincing gene, which was SCN2A, but they didn’t know if the genetic variants in this SCN2A gene were abnormal in their function.”

The colleague told Ducros about George, who as it turned out was one of the leading experts on SCN2A function – and a new collaboration was born.

“We both just happened to be in the room where someone knew both of us. So a little serendipity” is how the study came about, George said.

Ducros and colleagues first set their sights on a family in which six individuals had FHM that had started between the ages of 4 and 11 years. These affected family members showed transient motor deficits, sensory disturbances, and other symptoms followed by migraine headache. These individuals had “pure FHM,” defined as having normal neurological function between attacks, without the permanent cerebellar signs and other symptoms of the second main clinical form of the disorder.

To identify potential new genetic variants at play in this family, the researchers performed whole-genome linkage analysis, a type of genetic mapping, along with partial exome sequencing, which examines specific protein-coding regions of genes.

That led to the identification of three rare variants, one of which was SCN2A. It made sense for the researchers to then focus on that particular variant, considering that SCN2A encodes a sodium channel widely expressed in the brain including the cerebellum, and because it is associated with paroxysmal neurological disorders.

It turned out that all of the family members who had FHM had the SCN2A variant, while unaffected family members did not. This particular variant was a missense mutation, in which one amino acid is substituted for another in the ion channel. The investigators then screened individuals from six additional FHM families, which allowed them to identify a different SCN2A variant in one of those families. Finally, they looked at nearly 600 unrelated patients with FHM or sporadic HM, leading to discovery of a third variant in a sporadic case.

A familiar gene with a new role
George told Migraine Science Collaborative that while SCN2A had not previously been linked to FHM, it was nonetheless a familiar ion channel.

“A lot was known about SCN2A dating back many years when it was first identified in families that had a relatively limited epilepsy syndrome that was passed on from parent to child. It was always associated with seizures that started during infancy, but the kids would reach an age where the seizures just stopped,” George said, adding that they had normal neurodevelopment and intellectual development.

But soon after that, George continued, SCN2A was linked to more severe cases, where seizures were associated with serious neurodevelopmental consequences and even sudden death. In more recent decades, the gene has been discovered to play a leading role in autism. Researchers also know that SCN2A is involved with some movement disorders.

So, for his part of the study, George and his colleagues first performed electrophysiology experiments to understand how the newly identified SCN2A variants might affect the function of the ion channel. Here, the investigators expressed the variants in a cell line and examined their effects on different electrical properties.

A number of complex abnormalities became apparent, which made it difficult to understand what the overall contribution of the variants was to the electrical excitability of the cells. Sometimes when an ion channel has a mutation, the effect is an enhancement of channel activity; this is known as a gain-of-function mutation. In other instances, the channel loses some or all of its ability to function, which is called a loss-of-function mutation. But the SCN2A variants did not fit into this neat classification scheme.

“Some measured properties of the channel would classify it as gain of function, whereas other [properties] tilt the other way,” George said.

The group also wanted to know what effects the variants would have specifically on a nerve cell.

“We couldn’t intuitively make the leap from our simple studies of the channel itself to what would happen in an intact neuron. And that was why we brought on computational approaches,” according to George.

Modeling what a neuron does
To do so, George said, “we first started out with designing essentially a mathematical model of a neuron that can fire action potentials. That’s not new – people have been modeling neurons computationally for decades. My student wanted to make a better model.”

That student was Syed Wafa, a graduate student in George’s lab, and one of the co-first authors on the new study along with Florence Riant, Saint-Louis Hospital, Paris, France, and Christopher Thompson, Northwestern University Feinberg School of Medicine. To design that better model, Wafa began by creating a model that simulated the effects of two SCN2A mutations that had been associated with seizures or neurodevelopmental disease in previous studies.

The next step was to tweak the model so that it resembled what was wrong with the variants the researchers had identified in the new study.

“He changed all of [the model’s] properties to the extent that he could, so that it mimicked what the experiments told us was wrong with the mutant SCN2A. And he did that for each of the three mutations; they’re all a little different,” George said.

One other important aspect of the model, George added, was that it took into account that the SCN2A variants identified in the new research were heterozygous, meaning that the affected individuals had one normal copy of the gene, and one mutant version. Most of the time, George said, computational models of ion channel function simplify the situation by assuming that all channels are mutated ones.

The new computational model showed that the net effect of all the changes in the variant channels was an increase in electrical excitability, which the investigators think is how the variants contribute to the phenotype of the FHM patients and the sporadic case.

“A druggable target”
Going forward, Helbig said, the big question is how applicable the findings of the study might be to the wider population of HM patients.

“What I think we would want to see next is whether this is an ultra-rare finding [or] whether this is somewhat reproducible across the larger hemiplegic migraine population…. Is this a biological one-off? Or are we looking at a new pattern that would eventually help us explain this and tailor treatments in the population more broadly?” Helbig said.

Helbig again pointed to the challenge of finding HM patients in the first place, particularly those with mild forms of the condition.

“I think the systematic search for causes in people who have hemiplegic migraines that are not extremely severe hasn’t been started yet – I would probably say that 90-plus percent of people who have mild hemiplegic migraine have not been assessed for this,” he said.

For his part, George said he is interested in learning what additional fruit the modeling work might bear.

“Because we have this computational model, which we’ve used successfully for these three mutations, we’re now starting to look at other mutations and how they behave and how they compare,” he said. “Is there some logic behind why these three in particular are associated with hemiplegic migraine, whereas some others are not?”

George emphasized that SCN2A deserves more scrutiny.

“We’ve come to learn that SCN2A is a super important gene in the brain. And even subtle abnormalities in this can lead to pretty devastating consequences that can be lifelong and impair people neurologically. It’s one of those genes that needs a lot more attention,” he said.

George said it’s possible that there are still-to-be-discovered roles for SCN2A in other neurological diseases – including adult conditions.

“Most of the SCN2A studies are motivated by diagnoses in children. So what kind of adult disorders are we completely missing – because we’re not doing genetic testing in everybody…. Might we find SCN2A and other ion channel mutations in a larger segment of the population?”

The payoff of this better understanding of SCN2A could be huge.

“Ion channels, as a general class of proteins, are druggable. There are amazing opportunities to develop drugs to correct functional mutations in genes like SCN2A. So I feel like there’s a reason to do the genetics and that is, we may find opportunities for more precise treatment,” George said.

Neil Andrews is a science journalist and executive editor of the Migraine Science Collaborative.

Image credit: 123RF Stock Photo.

Reference
SCN2A variants are associated with familial and sporadic hemiplegic migraine.
Riant et al.
Brain. 2026 Mar 26:awag109. Online ahead of print