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When a newborn begins having seizures within the first days or weeks of life, the hours and days that follow can be among the most frightening a family will ever face. For some of these families, genetic testing will eventually return a result pointing to the SCN2A gene — and more specifically, to what researchers call a gain of function (GOF) variant. If your family has received this diagnosis, this guide is written for you.
Understanding what a GOF variant means — how it differs from other types of SCN2A mutations, what it means for your child’s care, and what the research community is doing about it — is one of the most empowering steps you can take. Start with the basics of understanding the SCN2A gene, and then read on for a plain-language explanation of the GOF side of the SCN2A spectrum.
The SCN2A gene carries the instructions for building a protein called Nav1.2 — a voltage-gated sodium channel embedded in the surface of neurons (brain cells). Nav1.2’s job is to act as a precisely regulated gateway, opening briefly to allow sodium ions to rush into the neuron, generating the electrical signal that neurons use to communicate. This process — called an action potential — is the fundamental unit of brain activity.
Nav1.2 is particularly active during early brain development. It is expressed at high levels in excitatory neurons — the cells responsible for sending “on” signals throughout the brain — during the neonatal and early infantile periods. During development, Nav1.2 is later partially replaced by Nav1.6 in key neuronal regions, which contributes to age-dependent changes in SCN2A-related phenotypes. Because of this developmental timing, mutations that alter Nav1.2 function can have profound effects on how the brain organizes and regulates itself in the critical first months of life.
A gain of function (GOF) mutation causes the Nav1.2 channel to become overactive. Instead of opening and closing in its carefully timed pattern, the channel allows excess sodium current to flow into the neuron — or fails to shut off properly. These changes alter channel gating in ways that increase neuronal excitability, even if total sodium current is not always increased. This tips neurons into a state of hyperexcitability: they fire more readily, more frequently, and with less provocation than they should.
The biophysical changes underlying GOF variants can take several forms. Some variants slow the channel’s process of inactivation — the mechanism by which it closes after firing. Others accelerate recovery, meaning the channel is ready to fire again sooner than it should be. Still others increase what researchers call persistent sodium current — a small but continuous flow of sodium that, when elevated, chronically raises neuronal excitability. The common thread across all of these mechanisms is the same: the channel is doing too much, and the brain’s electrical system tips out of balance. The impact of GOF variants can vary depending on developmental stage and neuron type, which contributes to changes in seizure patterns over time.
Many SCN2A GOF variants arise as de novo mutations — genetic changes that occur spontaneously and are not inherited from either parent. They are typically identified through genetic testing such as whole-exome sequencing or targeted epilepsy gene panels.
SCN2A variants exist on a functional spectrum. At one end, gain of function (GOF) variants make the Nav1.2 channel overactive — producing neuronal hyperexcitability and early-onset seizures. At the other end, loss of function (LOF) variants reduce channel activity, and are associated with autism spectrum disorder, intellectual disability, and later-onset or no epilepsy. Mixed function variants fall between these poles, showing some GOF and some LOF characteristics across different electrophysiological measures.
Research analyzing the relationship between variant function and clinical presentation in large SCN2A cohorts has found that GOF and mixed function variants predominate in neonatal-onset epilepsy, while more severe LOF variants are associated with later-onset epilepsy and autism. This genotype-phenotype relationship — the connection between a variant’s biological effect and a child’s clinical presentation — is one of the better-characterized genotype–phenotype relationships in rare neurodevelopmental disorders.
The distinction is not just academic. It directly shapes which care approaches are appropriate for a given child, and which research programs are most relevant to their diagnosis. A child with a GOF variant has a fundamentally different biology than a child with a LOF variant, and that difference matters at every stage of care planning.
Not all SCN2A GOF presentations are severe. At the milder end of the spectrum, some children with GOF variants develop self-limited neonatal or infantile epilepsy — seizures that begin in the first weeks or months of life but often improve over time, with many children having favorable developmental outcomes, though some may still experience subtle developmental differences. These children may respond well to anti-seizure medications during the active seizure period, and many go on to have largely typical neurodevelopmental trajectories.
This milder presentation reflects the fact that GOF variants are not a single, uniform entity — they span a range of functional severity. The degree to which a variant disrupts normal Nav1.2 gating, and the specific biophysical mechanism involved, shape how the clinical picture unfolds for each child.
At the more severe end of the GOF spectrum is developmental and epileptic encephalopathy (DEE) — a category of early-onset disorders characterized by seizures that are frequent, difficult to control, and accompanied by significant impacts on development. In SCN2A GOF DEE, seizures most commonly begin in the neonatal or early infantile period, often within the first months of life, and in many cases within the first days.
Epilepsy syndromes reported in association with SCN2A GOF DEE include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures (EIMFS), and West syndrome, among others. Children with these presentations often experience clusters of focal seizures, may progress through different seizure types as they develop, and frequently face challenges beyond seizure control — including movement difficulties, hypotonia, and gastrointestinal symptoms.
It is important for families to understand that the clinical trajectory is not fixed. Seizure frequency and character can evolve over time, and the relationship between seizure burden and developmental outcome is complex and varies between individual children. A multidisciplinary care team — including a neurologist experienced in genetic epilepsies, a geneticist, and developmental specialists — is central to navigating this landscape. You can explore active SCN2A research that is advancing understanding of these presentations and their underlying mechanisms.
Because SCN2A GOF variants cause the Nav1.2 channel to be overactive, the therapeutic rationale often supports approaches that reduce sodium channel activity. A class of anti-seizure medications known as sodium channel blockers (SCBs) — which includes medications such as phenytoin, oxcarbazepine, and carbamazepine — have been used in the management of seizures in some children with early-onset SCN2A GOF presentations, and some children have shown meaningful responses.
This stands in direct contrast to SCN2A loss of function disorders, where the channel is already underactive and sodium channel blockers are not appropriate. Getting the variant classification right — GOF versus LOF — is therefore clinically essential. Families can discuss with their care team whether functional characterization data are available for their child’s variant and whether additional functional testing may be indicated.
Anti-seizure medication management in SCN2A GOF DEE is complex and should always be guided by a specialist with experience in genetic epilepsies. No medication should be started, stopped, or changed without medical supervision. The goal of current standard care is seizure reduction and quality of life support — and the emerging research pipeline described below offers genuine hope for approaches that go further.
One of the most advanced targeted therapies currently in development for SCN2A GOF disorders is an antisense oligonucleotide (ASO) called elsunersen (also known as PRAX-222), being developed by Praxis Precision Medicines. An ASO is a short, engineered strand of genetic material designed to reduce SCN2A expression by targeting its RNA, which in turn reduces the quantity of overactive Nav1.2 channels in neurons. The goal is to bring channel activity back toward a normal level, addressing the underlying GOF mechanism rather than just managing symptoms.
Elsunersen has received Orphan Drug Designation and Rare Pediatric Disease Designation from the U.S. Food and Drug Administration (FDA), and Orphan Drug and PRIME designations from the European Medicines Agency (EMA). A Phase 1/2 study called EMBRAVE Part A, which enrolled 9 participants (7 receiving elsunersen and 2 receiving placebo), reported topline results in April 2026. In that small early-stage study, participants who received elsunersen had a 77% placebo-adjusted reduction in motor seizures (p=0.0152). Because this result comes from a very small cohort, it should be interpreted with caution — but it represents an encouraging early signal for the program.
A Phase 3 registrational trial called EMBRAVE3 is now enrolling in the United States (including sites in California, Illinois, Ohio, Colorado, Tennessee, and Pennsylvania) and is expanding internationally. In a design aligned with the FDA, EMBRAVE3 is a single-arm, baseline-controlled study — a design commonly used in rare disease settings but without a concurrent placebo control group — meaning every child enrolled receives the active treatment. Families interested in whether their child may be eligible are encouraged to discuss with their neurologist and visit www.embravestudy.com for current enrollment information.
A second therapy in development for SCN2A GOF DEE is relutrigine (PRAX-562), a small molecule sodium channel modulator also being developed by Praxis Precision Medicines. Unlike an ASO — which reduces gene expression — relutrigine works at the level of the channel itself, targeting a specific channel state to reduce pathological neuronal hyperexcitability. Praxis has submitted a New Drug Application (NDA) for relutrigine to the FDA, with Priority Review designation reported by the sponsor. Families and clinicians can follow developments through their care team and the Foundation’s research updates.
Both programs represent a meaningful shift in how the field is approaching SCN2A GOF disorders — moving from broad symptom management toward therapies designed around the specific biology of the mutation. This precision medicine approach is the future the SCN2A community has been working toward, and families who join the patient registry help make it possible. Join the SCN2A patient registry to connect your child’s data to the research that will shape the next generation of therapies.
The research momentum building around SCN2A gain of function disorders is real — but bringing targeted therapies from clinical trials to families requires sustained investment, a growing evidence base, and a connected community of families willing to contribute their experiences to science.
Every family navigating an SCN2A gain of function diagnosis deserves answers, community, and hope. The work to find them depends on your support. Please consider making a donation to help fund the research and resources that move us all forward.
This content is provided for educational and informational purposes only and does not constitute medical advice. The information on this page is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the guidance of a qualified healthcare provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
7. Praxis Precision Medicines. EMBRAVE3 Study Information.
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When a newborn begins having seizures within the first days or weeks of life, the hours and days that follow can be among the most frightening a family will ever face. For some of these families, genetic testing will eventually return a result pointing to the SCN2A gene — and more specifically, to what researchers call a gain of function (GOF) variant. If your family has received this diagnosis, this guide is written for you.
Understanding what a GOF variant means — how it differs from other types of SCN2A mutations, what it means for your child’s care, and what the research community is doing about it — is one of the most empowering steps you can take. Start with the basics of understanding the SCN2A gene, and then read on for a plain-language explanation of the GOF side of the SCN2A spectrum.
The SCN2A gene carries the instructions for building a protein called Nav1.2 — a voltage-gated sodium channel embedded in the surface of neurons (brain cells). Nav1.2’s job is to act as a precisely regulated gateway, opening briefly to allow sodium ions to rush into the neuron, generating the electrical signal that neurons use to communicate. This process — called an action potential — is the fundamental unit of brain activity.
Nav1.2 is particularly active during early brain development. It is expressed at high levels in excitatory neurons — the cells responsible for sending “on” signals throughout the brain — during the neonatal and early infantile periods. During development, Nav1.2 is later partially replaced by Nav1.6 in key neuronal regions, which contributes to age-dependent changes in SCN2A-related phenotypes. Because of this developmental timing, mutations that alter Nav1.2 function can have profound effects on how the brain organizes and regulates itself in the critical first months of life.
A gain of function (GOF) mutation causes the Nav1.2 channel to become overactive. Instead of opening and closing in its carefully timed pattern, the channel allows excess sodium current to flow into the neuron — or fails to shut off properly. These changes alter channel gating in ways that increase neuronal excitability, even if total sodium current is not always increased. This tips neurons into a state of hyperexcitability: they fire more readily, more frequently, and with less provocation than they should.
The biophysical changes underlying GOF variants can take several forms. Some variants slow the channel’s process of inactivation — the mechanism by which it closes after firing. Others accelerate recovery, meaning the channel is ready to fire again sooner than it should be. Still others increase what researchers call persistent sodium current — a small but continuous flow of sodium that, when elevated, chronically raises neuronal excitability. The common thread across all of these mechanisms is the same: the channel is doing too much, and the brain’s electrical system tips out of balance. The impact of GOF variants can vary depending on developmental stage and neuron type, which contributes to changes in seizure patterns over time.
Many SCN2A GOF variants arise as de novo mutations — genetic changes that occur spontaneously and are not inherited from either parent. They are typically identified through genetic testing such as whole-exome sequencing or targeted epilepsy gene panels.
SCN2A variants exist on a functional spectrum. At one end, gain of function (GOF) variants make the Nav1.2 channel overactive — producing neuronal hyperexcitability and early-onset seizures. At the other end, loss of function (LOF) variants reduce channel activity, and are associated with autism spectrum disorder, intellectual disability, and later-onset or no epilepsy. Mixed function variants fall between these poles, showing some GOF and some LOF characteristics across different electrophysiological measures.
Research analyzing the relationship between variant function and clinical presentation in large SCN2A cohorts has found that GOF and mixed function variants predominate in neonatal-onset epilepsy, while more severe LOF variants are associated with later-onset epilepsy and autism. This genotype-phenotype relationship — the connection between a variant’s biological effect and a child’s clinical presentation — is one of the better-characterized genotype–phenotype relationships in rare neurodevelopmental disorders.
The distinction is not just academic. It directly shapes which care approaches are appropriate for a given child, and which research programs are most relevant to their diagnosis. A child with a GOF variant has a fundamentally different biology than a child with a LOF variant, and that difference matters at every stage of care planning.
Not all SCN2A GOF presentations are severe. At the milder end of the spectrum, some children with GOF variants develop self-limited neonatal or infantile epilepsy — seizures that begin in the first weeks or months of life but often improve over time, with many children having favorable developmental outcomes, though some may still experience subtle developmental differences. These children may respond well to anti-seizure medications during the active seizure period, and many go on to have largely typical neurodevelopmental trajectories.
This milder presentation reflects the fact that GOF variants are not a single, uniform entity — they span a range of functional severity. The degree to which a variant disrupts normal Nav1.2 gating, and the specific biophysical mechanism involved, shape how the clinical picture unfolds for each child.
At the more severe end of the GOF spectrum is developmental and epileptic encephalopathy (DEE) — a category of early-onset disorders characterized by seizures that are frequent, difficult to control, and accompanied by significant impacts on development. In SCN2A GOF DEE, seizures most commonly begin in the neonatal or early infantile period, often within the first months of life, and in many cases within the first days.
Epilepsy syndromes reported in association with SCN2A GOF DEE include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures (EIMFS), and West syndrome, among others. Children with these presentations often experience clusters of focal seizures, may progress through different seizure types as they develop, and frequently face challenges beyond seizure control — including movement difficulties, hypotonia, and gastrointestinal symptoms.
It is important for families to understand that the clinical trajectory is not fixed. Seizure frequency and character can evolve over time, and the relationship between seizure burden and developmental outcome is complex and varies between individual children. A multidisciplinary care team — including a neurologist experienced in genetic epilepsies, a geneticist, and developmental specialists — is central to navigating this landscape. You can explore active SCN2A research that is advancing understanding of these presentations and their underlying mechanisms.
Because SCN2A GOF variants cause the Nav1.2 channel to be overactive, the therapeutic rationale often supports approaches that reduce sodium channel activity. A class of anti-seizure medications known as sodium channel blockers (SCBs) — which includes medications such as phenytoin, oxcarbazepine, and carbamazepine — have been used in the management of seizures in some children with early-onset SCN2A GOF presentations, and some children have shown meaningful responses.
This stands in direct contrast to SCN2A loss of function disorders, where the channel is already underactive and sodium channel blockers are not appropriate. Getting the variant classification right — GOF versus LOF — is therefore clinically essential. Families can discuss with their care team whether functional characterization data are available for their child’s variant and whether additional functional testing may be indicated.
Anti-seizure medication management in SCN2A GOF DEE is complex and should always be guided by a specialist with experience in genetic epilepsies. No medication should be started, stopped, or changed without medical supervision. The goal of current standard care is seizure reduction and quality of life support — and the emerging research pipeline described below offers genuine hope for approaches that go further.
One of the most advanced targeted therapies currently in development for SCN2A GOF disorders is an antisense oligonucleotide (ASO) called elsunersen (also known as PRAX-222), being developed by Praxis Precision Medicines. An ASO is a short, engineered strand of genetic material designed to reduce SCN2A expression by targeting its RNA, which in turn reduces the quantity of overactive Nav1.2 channels in neurons. The goal is to bring channel activity back toward a normal level, addressing the underlying GOF mechanism rather than just managing symptoms.
Elsunersen has received Orphan Drug Designation and Rare Pediatric Disease Designation from the U.S. Food and Drug Administration (FDA), and Orphan Drug and PRIME designations from the European Medicines Agency (EMA). A Phase 1/2 study called EMBRAVE Part A, which enrolled 9 participants (7 receiving elsunersen and 2 receiving placebo), reported topline results in April 2026. In that small early-stage study, participants who received elsunersen had a 77% placebo-adjusted reduction in motor seizures (p=0.0152). Because this result comes from a very small cohort, it should be interpreted with caution — but it represents an encouraging early signal for the program.
A Phase 3 registrational trial called EMBRAVE3 is now enrolling in the United States (including sites in California, Illinois, Ohio, Colorado, Tennessee, and Pennsylvania) and is expanding internationally. In a design aligned with the FDA, EMBRAVE3 is a single-arm, baseline-controlled study — a design commonly used in rare disease settings but without a concurrent placebo control group — meaning every child enrolled receives the active treatment. Families interested in whether their child may be eligible are encouraged to discuss with their neurologist and visit www.embravestudy.com for current enrollment information.
A second therapy in development for SCN2A GOF DEE is relutrigine (PRAX-562), a small molecule sodium channel modulator also being developed by Praxis Precision Medicines. Unlike an ASO — which reduces gene expression — relutrigine works at the level of the channel itself, targeting a specific channel state to reduce pathological neuronal hyperexcitability. Praxis has submitted a New Drug Application (NDA) for relutrigine to the FDA, with Priority Review designation reported by the sponsor. Families and clinicians can follow developments through their care team and the Foundation’s research updates.
Both programs represent a meaningful shift in how the field is approaching SCN2A GOF disorders — moving from broad symptom management toward therapies designed around the specific biology of the mutation. This precision medicine approach is the future the SCN2A community has been working toward, and families who join the patient registry help make it possible. Join the SCN2A patient registry to connect your child’s data to the research that will shape the next generation of therapies.
The research momentum building around SCN2A gain of function disorders is real — but bringing targeted therapies from clinical trials to families requires sustained investment, a growing evidence base, and a connected community of families willing to contribute their experiences to science.
Every family navigating an SCN2A gain of function diagnosis deserves answers, community, and hope. The work to find them depends on your support. Please consider making a donation to help fund the research and resources that move us all forward.
This content is provided for educational and informational purposes only and does not constitute medical advice. The information on this page is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the guidance of a qualified healthcare provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
7. Praxis Precision Medicines. EMBRAVE3 Study Information.
Vlad Magdalin
