Epilepsy Gene Implicated in Severe Migraine Disorder
By - Olivia Dimmer
Investigators led by Northwestern Medicine scientists have identified mutations in a gene coding for a key ion channel in the brain as a new cause of a debilitating form of migraine, according to a study published in Brain.
Familial hemiplegic migraine (FHM), a rare and severe form of migraine, is marked by temporary paralysis or weakness on one side of the body during attacks. Although the disorder runs in families, known migraine-linked genes explained fewer than one in five genetically diagnosed cases, said Alfred L. George, Jr., MD, chair and the Alfred Newton Richards Professor of Pharmacology, who was co-corresponding author of the study.
“Patients with this type of migraine have a dramatic symptom before the onset of the headache: they lose the ability to move their muscles on half their body (hemiplegia), which can be pretty scary. And often, it’s assumed to be a stroke until proven otherwise,” George said.
The new genetic study revealed evidence that mutations in the gene SCN2A — which was previously associated with epilepsy and neurodevelopmental disorders, including autism spectrum disorder — can also cause both familial and sporadic hemiplegic migraine. The findings expand the genetic landscape of migraine and add to the growing list of neurological conditions linked to SCN2A dysfunction.
To uncover new genetic causes of FHM, investigators studied a large, four-generation family affected by hemiplegic migraine using whole-genome linkage analysis and targeted exome sequencing. Their search pointed to a single candidate: SCN2A, which encodes the neuronal voltage-gated sodium channel Nav1.2, a crucial component of electrical signaling in the brain.
The team identified a rare mutation in SCN2A that was present in all affected family members and absent in unaffected relatives. To determine whether the finding extended beyond one family, the investigators screened additional families with multiple affected individuals, as well as nearly 600 unrelated patients with hemiplegic migraine who lacked mutations in known FHM genes.
That expanded search uncovered two more rare SCN2A variants — one in another affected family and one in a sporadic case. None of the variants had previously been reported in a large population genetics database, strengthening the case that they are disease-causing rather than benign genetic variations.
To test whether the identified variants altered ion channel function, the scientists conducted electrophysiological recording experiments. All three SCN2A mutations changed how the sodium channel responded to voltage and how quickly it activated and inactivated — key properties that determine how neurons fire. To explore how mutant SCN2A affects neurons, the investigators conducted computer simulations.
“The behavior of the mutant channels predisposes computer-simulated neurons to become hyperactive, or hyper-excitable — more easily triggered to fire and fire longer,” George said.
The findings suggest that certain SCN2A mutations may selectively disrupt brain activity in a way that predisposes individuals to hemiplegic migraine attacks without causing broader, long-term neurological impairment.
“My lab has been studying SCN2A for more than 20 years, and helped establish how this one gene is able to produce a wide range of neurological findings,” George said. “From epilepsy starting in neonates, to autism, and perhaps hemiplegic migraine is just one more expression of what happens when nature tinkers with SCN2A.”
The discovery places SCN2A alongside a small but growing group of ion channel genes implicated in migraine and reinforces the idea that migraine is fundamentally a disorder of brain excitability, George said. It also broadens knowledge of SCN2A-related disease.
The findings may eventually improve genetic diagnosis and counseling, George said. More broadly, the study adds momentum to efforts to better understand migraine at a molecular level — knowledge that could ultimately inform new therapies.
Additional Feinberg co-authors included Christopher Thompson, PhD, research associate professor of Pharmacology, and Syed Mohammad Adil Wafa, a PhD student in the Northwestern University Interdepartmental Neuroscience (NUIN) program.
Anne Ducros, MD, professor of Neurology at the University of Montpellier, was a co-corresponding author of the study and led the genetic mapping.
“This work would not happen without the ability to work with people in another country,” George said. “Science is not an Olympic sport where we all stay within our countries. It is a global team sport.”