A handful of families from around the world with a rare brain malformation called polymicrogyria have led scientists to discover a new gene that helps us speak and swallow.
The gene, SCN3A, is turned “on” primarily during fetal brain development. When it’s mutated, a language area of the brain known as the perisylvian cortex develops multiple abnormally small folds, appearing bumpy. People with polymicrogyria in this region often have impaired oral motor development, including difficulties with swallowing, tongue movement and articulating words — especially if the polymicrogyria affects both sides of the brain.
The new study, published today in Neuron, ties together human genetics, measurements of electrical currents generated by neurons, studies of ferrets and more to start to connect the dots between SCN3A, the brain malformation and the oral motor impairment.
“Speech delay and swallowing difficulties are relatively common,” says Maria Lehtinen, PhD, a pathologist in the Neurobiology Program at Boston Children’s Hospital who co-led the study. “The fact that we can pair this with hereditary structural changes in the brain allows the unpacking of the condition. We anticipate our study will open doors to better understanding these developmental processes.”
Embarking on the journey
For Lehtinen, the finding caps a journey that began with a single family in her native Finland. It was 2006, and she was working in an epilepsy genetics lab. A family had come in because of problems with swallowing and speech, telling the neurologist, “It seems like we have more of this than other families.”
“In Finland, because the population is so isolated, it’s common to do genetic studies,” says Lehtinen. “This was the largest multigenerational family with this presentation documented in the world. Our lab wanted to identify the gene that underlies their disorder.”
But the proper tools didn’t yet exist. The researchers weren’t even sure if the inheritance pattern was dominant or recessive. Finding similar families with a clear inheritance pattern that might point a possible shared mutation proved difficult.
Cracking the case
Lehtinen began to crack the case when she left Finland for the Boston Children’s lab of Christopher Walsh, MD, PhD, who is co-senior author on the Neuron paper and chief of genetics and genomics at Boston Children’s.
As a personal twist to the story, Lehtinen’s colleague in Montreal (and mother-in-law), Eva Andermann, had identified two French Canadian families with similar oral motor difficulties. These were pooled with two other cases from the Walsh lab: a family from the United Arab Emirates with the same symptoms, and a Pennsylvania family enrolled in Walsh lab research. The European Epilepsy Consortium also identified a family from Holland.
Using advanced genetic technologies, Lehtinen and Walsh sequenced the entire Finnish family (Family A above), and, later, the other families. However, they still didn’t know how a mutation in SCN3A, a gene that encodes sodium channels (tiny portals that let sodium ions flow into neurons), could be causing the speech and swallowing problems.
“We wanted to test out what was going on in the ion channel,” Lehtinen says. “That’s when Richard Smith, a card-carrying electrophysiologist, came in.”
Going with the current
Smith, first author on the paper, had joined the Walsh Lab in late 2015. He is an expert in measuring the tiny electrical currents generated by neurons as they fire off action potentials. Smith says “I immediately saw the potential to study these patients’ mutations using patch clamp, an experimental approach that allowed for a clear biophysical description of the diseased channel.”
At that point, the team consulted two resources that had since become available: the Allen Brain Atlas, as well as single-cell RNA sequencing data from the developing brain provided by Alex Pollen of the University of California San Francisco. From these, they learned that SCN3A is primarily active during fetal brain development.
Lehtinen thinks that explains an interesting paradox. The related SCN1A and SCN2A genes are closely linked to epilepsy, often severe early-onset forms, such as Dravet syndrome. Yet the families with SCN3A mutations mostly don’t have epilepsy, although they commonly do have intellectual disability, developmental delay, receptive language problems and other deficits.
Lehtinen speculates that neurons are too immature during fetal development, when SCN3A is most active, to develop the abnormalities associated with epilepsy. The location of the mutations on the gene might also play a role.
Ferreting out SCN3A’s role in brain development
The ferret studies were what nailed it. Unlike mice, ferrets have folds in their brains that are similar to those in humans. So, the team deliberately mutated SCN3A and placed the diseased associated version into ferret brains. The animals’ brains developed a folding pattern closely mirroring human polymicrogyria — as seen on miniature MRI systems designed for small animals using Boston Children’s small animal imaging core.
Lehtinen and colleagues then dug deeper, examining brain slices under the microscope. They saw that the expected migration of immature neurons toward the outer brain was disrupted.
“They don’t make it to the part of cortex where they should be,” Lehtinen explains. “We think that an impaired current in immature neurons disrupts how much they are sensing, and that this disrupts their normal migration. At the time when SCN3A is active, many progenitor neurons are being produced. If you have disruption in their movement, they migrate over and on top of each other – like a domino effect.”
Disrupted speech circuits?
The researchers theorize that the resulting structural malformation disrupts the circuitry that innervates the brain’s speech motor areas. Lehtinen notes that the malformed part of the brain controls key speech-generating functions, such as proper tongue movement.
“We don’t yet have a handle on what the exact mechanisms are,” says Smith. “We are just beginning to understand evolution’s plan for this gene in growing the human brain and in developing speech.”
Unlike epilepsy, which can sometimes be treated with sodium channel-blocking drugs, the speech and swallowing problems caused by SCN3A mutations are already hard-wired in brain structure. “To really intervene you’d probably need a CRISPR-based gene therapy approach early in life,” says Lehtinen. “At this moment, speech therapy and physical therapy are the main options.”
The study was supported by the National Institutes of Health (1F32NS100033801, NIH R01NS032457 and R01NS035129); the Erasmus MC Mrace project (104673); the Finnish Medical Society; the Arvo and Lea Ylppö Foundation; the Finnish government (TLK0278, TRTR019); the Folkhälsan Research Foundation; the Paul G. Allen Frontiers Program, the New York Stem Cell Foundation, the Boston Children’s Hospital IDDRC (1U54HD090255), the Howard Hughes Medical Institute.
Lehtinen is a Robertson Investigator of the New York Stem Cell Foundation and an affiliate faculty member of the Harvard Stem Cell Institute (HSCI). Walsh is also a Howard Hughes Medical Institute Investigator and a principal faculty member of the HSCI. See the paper for a full list of affiliations.