Summary: Researchers identify SCN3A gene mutations as a cause of early infantile epileptic encephalopathy.
Source: CHOP.
Researchers have identified mutations in the SCN3A gene that underlie a severe form of infant epilepsy and provide initial evidence that certain anti-seizure medications may reduce early brain injury by suppressing pathological electrical activity in a critical newborn window.
“These findings are preliminary but promising: understanding how these mutations affect the newborn brain could allow us to prevent lasting injury and improve long-term outcomes,” said study leader Ethan M. Goldberg, MD, PhD, a pediatric neurologist at the Children’s Hospital of Philadelphia.
Goldberg and international collaborators described this neurogenetic work, focused on early infantile epileptic encephalopathy, in a paper published online on February 21, 2018 in Annals of Neurology.
The research concentrated on SCN3A, the gene that encodes the Nav1.3 voltage-gated sodium channel. SCN3A has a distinctive expression pattern in the brain during late gestation and the neonatal period. While prior studies had linked SCN3A variants to milder epilepsies, this study provides the first clear evidence that specific de novo SCN3A mutations cause the most severe early infantile epileptic encephalopathy.
Sodium channels regulate the flow of sodium ions into neurons and are essential for generating and propagating action potentials—the electrical signals that mediate communication across neural circuits. Three other sodium channel genes expressed in brain (encoding Nav1.1, Nav1.2 and Nav1.6) were already known to cause genetic epilepsies when mutated. Nav1.3, encoded by SCN3A, had been the remaining channel without a confirmed link to severe infantile epilepsy, making it a sought-after “missing” cause. The new study implicates SCN3A gain-of-function mutations as an additional molecular cause of early infantile epileptic encephalopathy.
“We found gain-of-function changes in SCN3A,” Goldberg explained. “These mutations increase channel activity by producing a persistent current—channels remain abnormally open and allow continuous sodium influx. That overactivity appears to drive the epileptic encephalopathy seen in affected infants.”
The team reported four unrelated infants from different countries, each with treatment-resistant seizures beginning within the first two weeks of life. All four children developed severe to profound developmental impairment, and two of the cases with the same variant showed diffuse brain malformations consistent with polymicrogyria. Seizures were refractory to standard therapies and resulted in substantial, lifelong disability.
Researchers used whole-exome sequencing to detect heterozygous, de novo missense variants in SCN3A (not inherited from either parent). The specific variants identified in this cohort were p.Ile875Thr (found in two unrelated patients), p.Pro1333Leu, and p.Val1769Ala. Electrophysiological studies in expression systems characterized the mutant channels’ biophysical behavior, revealing how the altered channels affect neuronal excitability.
Functional assays showed a prominent gain of channel function for the disease-associated variants: an increased amplitude of the slowly inactivating (persistent) current component, and for two variants (p.Ile875Thr and p.Pro1333Leu) a hyperpolarizing shift in the voltage dependence of activation. In contrast, some Nav1.3 variants that are inherited or presumed benign did not show these gain-of-function changes.
Importantly, cell-culture pharmacology demonstrated that two existing anti-seizure drugs—lacosamide and phenytoin—preferentially inhibited the persistent current carried by mutant Nav1.3 channels. These results raise the possibility that targeted use of such agents during the neonatal period could reduce pathological sodium influx and limit early brain injury, although clinical application will require much more study.
Translating these laboratory results into safe and effective treatments will demand further work in neuronal cultures and animal models. Such preclinical testing is essential to evaluate potential precision-medicine approaches and to determine dosage, timing, and safety before any clinical trials in infants. Meanwhile, identification of these SCN3A variants has already allowed the gene to be added to clinical epilepsy testing panels, improving the speed and accuracy of genetic diagnosis for affected families.
Goldberg emphasized the importance of early, precise diagnosis because Nav1.3 activity is prominent during a limited developmental window. “If we can detect pathogenic SCN3A mutations early and intervene within that neonatal window, we may have a chance to prevent long-term neurological injury and improve outcomes,” he said.
Funding: This work was supported by the National Institutes of Health (grant NS097633) and the Burroughs Wellcome Fund Career Award for Medical Scientists.
Source: John Ascenzi, Children’s Hospital of Philadelphia (CHOP).
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Original research: Published in Annals of Neurology (online, Feb 21, 2018). DOI: 10.1002/ana.25188
Abstract
Mutations in SCN3A cause early infantile epileptic encephalopathy
Objective: Voltage-gated sodium channels are central to action potential generation and neuronal excitability. Mutations in several sodium channel genes (SCN1A, SCN2A, SCN8A) and in accessory subunits (SCN1B) cause genetic epilepsies, but SCN3A (encoding Nav1.3) had not been established as a cause of early infantile epileptic encephalopathy despite its high expression in the developing brain. Here we describe four patients with severe, treatment-resistant epilepsy beginning in the first year of life and heterozygous de novo missense variants in SCN3A (p.Ile875Thr in two cases, p.Pro1333Leu, and p.Val1769Ala).
Methods: All patients showed early-onset, drug-resistant seizures and severe to profound intellectual disability; two of the cases with p.Ile875Thr also had diffuse polymicrogyria. The investigators used whole-exome sequencing to identify SCN3A variants and performed electrophysiological recordings in heterologous expression systems to analyze channel function.
Results: Disease-associated Nav1.3 variants produced a marked gain of function, characterized by an increased amplitude of the slowly inactivating (persistent) current component. Two variants (p.Ile875Thr and p.Pro1333Leu) also showed a leftward shift in activation voltage, making channels more likely to open at more hyperpolarized potentials. Inherited or presumed benign Nav1.3 variants did not exhibit these changes. Pharmacological testing revealed that phenytoin and lacosamide selectively reduced the slowly inactivating current in both wild-type and mutant Nav1.3 channels.
Interpretation: These data establish SCN3A as a gene responsible for infantile epileptic encephalopathy and point to a potential pharmacologic strategy targeting persistent Nav1.3 current. The results underscore Nav1.3’s important role in regulating excitability in the developing brain and offer new mechanistic insight into Nav1.3 slow inactivation.