GENE GUIDE

SCN2A-Related Syndrome

This guide is not meant to take the place of medical advice. Please consult with your doctor about your genetic results and health care choices. This Gene Guide was last updated on 2024. As new information comes to light with new research we will update this page. You may find it helpful to share this guide with friends and family members or doctors and teachers of the person who has SCN2A-Related Syndrome.
a doctor sees a patient

SCN2A-related syndrome is also called SCN2A-developmental and epileptic encephalopathy; self-limited neonatal/infantile epilepsy; episodic ataxia, type 9;andSCN2A-related disorder. For this webpage, we will be using the name SCN2A-related syndrome to encompass the wide range of variants observed in the people identified.

SCN2A–related syndrome happens when there are changes in the SCN2A gene. These changes can keep the gene from working as it should.

 

Key Role

The SCN2A gene produces a protein that sits on the surface of brain cells and allows sodium to enter the cell. This protein is important for brain cells to make and transmit signals between cells and is essential for brain cells to work properly.

Symptoms

Because SCN2A is important in brain activity, many people who have SCN2A-related syndrome have:

  • Seizures
  • Developmental delay, or intellectual disability, or both
  • Autism or features of autism
  • Movement problems
  • Lower than average muscle tone
  • Gastrointestinal problems
  • Brain changes seen on magnetic resonance imaging (MRI)
  • Eye or vision issues

Changes in the SCN2A gene may be associated with any of three different disorders:

  1. Infantile epileptic encephalopathy, or IEE: This condition is defined by seizures that begin before 1 year of age. There is also neurodevelopmental delay.
  2. Benign infantile familial seizures, or BIFS: In this condition, seizures begin before 1 year of age but usually stop by 2 years of age. Usually, the person has no long-term neuropsychiatric problems. This is the least common disorder associated with changes in the SCN2A gene.
  3. Autism and developmental delay: Up to one-third of people who have autism and developmental delay also develop late-onset seizures. Development concerns may increase over time.

Most but not all children who have SCN2A-related syndrome fit into one of these categories. Related conditions include schizophrenia, a movement disorder called late-onset episodic ataxia, and a seizure disorder called childhood-onset epileptic encephalopathy.

SCN2A-related syndrome is a genetic condition, which means that it is caused by variants in genes. Our genes contain the instructions, or code, that tell our cells how to grow, develop, and work. Every child gets two copies of the SCN2A gene: one copy from their mother’s egg, and one copy from their father’s sperm. In most cases, parents pass on exact copies of the gene to their child. But the process of creating the egg or sperm is not perfect. A change in the genetic code can lead to physical issues, developmental issues, or both. 

Sometimes a spontaneous variant happens in the sperm, egg or after fertilization. When a brand new genetic variant happens in the genetic code is called a ‘de novo’ genetic variant. The child is usually the first in the family to have the genetic variant.

De novo variants can take place in any gene. We all have some de novo variants, most of which don’t affect our health. But because SCN2A plays a key role in development, de novo variants in this gene can have a meaningful effect. 

Research shows that SCN2A-related syndrome is often the result of a de novo variant in SCN2A. Many parents who have had their genes tested do not have the SCN2A genetic variant found in their child who has the syndrome. In some cases, SCN2A-related syndrome happens because the genetic variant was passed down from a parent.

Autosomal dominant conditions

SCN2A-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in SCN2A they will likely have symptoms of SCN2A-related syndrome. For someone with an autosomal dominant genetic syndrome, every time they have a child there is a 50 percent chance they pass on the same genetic variant and a 50 percent chance they do not pass on the same genetic variant.

Autosomal Dominant Genetic Syndrome

GENE / gene
GENE / gene
Genetic variant that happens in sperm or egg, or after fertilization
GENE / gene
Child with de novo genetic variant
gene / gene
Non-carrier child
gene / gene
Non-carrier child

No parent causes their child’s SCN2A-related syndrome. We know this because no parent has any control over the gene changes that they do or do not pass on to their children. Please keep in mind that nothing a parent does before or during the pregnancy causes this to happen. The gene change takes place on its own and cannot be predicted or stopped.

Each family is different. A geneticist or genetic counselor can give you advice on the chance that this will happen again in your family.

The risk of having another child who has SCN2A-related syndrome depends on the genes of both biological parents. 

  • If neither biological parent has the same genetic variant found in their child, the chance of having another child who has the syndrome is on average 1 percent. This 1 percent chance is higher than the chance of the general population. The increase in risk is due to the very unlikely chance that more of the mother’s egg cells or the father’s sperm cells carry the same genetic variant. 
  • If one biological parent has the same genetic variant found in their child, the chance of having another child who has the syndrome is 50 percent. 

For a symptom-free brother or sister of someone who has SCN2A-related syndrome, the sibling’s risk of having a child who has SCN2A-related syndrome depends on the sibling’s genes and their parents’ genes. 

  • If neither parent has the same genetic variant causing SCN2A-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit SCN2A-related syndrome. 
  • If one biological parent has the same genetic variant causing SCN2A-related syndrome, the symptom-free sibling has a 50 percent chance of also having the same genetic variant. If the symptom-free sibling has the same genetic variant, their chance of having a child who has the genetic variant is 50 percent. 

For a person who has SCN2A-related syndrome, the risk of having a child who has the syndrome is about 50 percent.

As of 2024, about 714 people in the world with changes in the SCN2A gene have been found in a medical clinic. The first case of SCN2A-related syndrome was described in 2002.

People who have SCN2A-related syndrome generally don’t look different.

Epilepsy is common in people who have SCN2A-related syndrome. In some cases, seizures that are linked to SCN2A-related conditions cannot be controlled. But, for infants whose seizures begin before 3 months of age, a class of medication known as sodium channel blockers, such as phenytoin and carbamazepine, may be helpful (Wolff et al., 2017). Note that this is the opposite of best practice guidelines for neonatal seizures.

Children who have autism and developmental delay whose seizures begin after 12 months of age respond best to a different set of medications, including levetiracetam, benzodiazepines, and valproate.

Little information is available on how to best treat infants whose seizures begin between 3 and 12 months of age. Some studies suggest that sodium channel blockers are the best option. Other studies have found improvement with medications including lidocaine (Foster et al., 2017; Ogiwara et al., 2009), ethosuximide (Wolff et al., 2017), and acetazolamide (Leach et al., 2016; Liao et al., 2010). There is not enough data on these medications to give specific advice.

If seizures happen, consult a neurologist. There are many types of seizures, and not all types are easy to spot. To learn more, you can refer to resources such as the Epilepsy Foundation’s website: epilepsy.com/learn/types-seizures.

It is important to seek care and therapies to help the person’s brain and nervous system develop and operate as well as it can. Soon after diagnosis, this can include:

  • Physical exams and brain studies. An electroencephalogram, also called an EEG, measures the brain’s electrical activity and may show the overall electrical disturbances in the brain. This may lead to the use of antiepileptic medications.

At present, there is no specific advice about how to treat other symptoms.
A genetic diagnosis can help people decide on the best way to track the condition and manage therapies. Doctors can refer people to specialists for:

  • Genetics consults.
  • Development and behavior studies.
  • Gastrointestinal issues. Many children who have SCN2A-related syndrome have constipation, gastroesophageal reflux, or diarrhea.
  • Other issues, as needed.

A developmental pediatrician, neurologist, or psychologist can follow progress over time and can help:

  • Suggest the right therapies. This can include physical, occupational, speech, or behavioral therapy.
  • Guide individualized education plans (IEPs).

Specialists advise that therapies for SCN2A-related syndrome should begin as early as possible, ideally before a child begins school.

This section includes a summary of information from major published articles and the Simons Searchlight quarterly registry report. It highlights how many people have different symptoms. To learn more about the articles, see the Sources and references section of this guide.

Genetic variants in SCN2A-related syndrome result in a gain of function, a loss of function, or a mixed function of the SCN2A protein. It is not always obvious how a change in the SCN2A gene will affect the SCN2A protein. To better understand this requires testing in the research laboratory.

Researchers are working to understand the differences between gain of function and loss of function SCN2A variants. We have summarized the general understanding of the differences in people. There is a wide spectrum of clinical severity for both of these variants.

SCN2A gain of function variant, people tend to:

  • Be younger at the time seizures develop (before the age of 2 years)
  • Have seizures that improve with sodium channel blocking anti-seizure medications

SCN2A loss of function variant, people tend to:

  • Be older at the time seizures develop or not have seizures at all
  • Have seizures that worsen with sodium channel blocking anti-seizure medications
  • Have autism and or intellectual disability

Brain

Most people with SCN2A-related syndrome had seizures at some point in infancy or childhood. 

  • 69 out of 81 children had seizures (85 percent)

The 69 children studied with seizures had seizure onset categories in 3 developmental timeframes.

  • Onset in the neonatal time period (under 1 month of age)
  • Onset in infancy (1 month to 11 months of age)
  • Onset later in childhood (12 months of age and older)

Less than one-half of people had brain changes observed on magnetic resonance imaging (MRI). Some of the findings included dysplasia of frontal lobes, enlargement of the ventricle, shrinking of the corpus callosum, and delayed white matter myelination.

  • 29 out of 72 children had findings on MRI (40 percent)

Speech and Learning

Most people with SCN2A-related syndrome had developmental delay or intellectual disability and language delay.

  • 111 out of 130 people had developmental delay or intellectual disability (85 percent)
  • 93 out of 130 people had language delay (72 percent)

Behavior

Some people with SCN2A-related syndrome had autism, attention deficit hyperactivity disorder (ADHD), or anxiety.

  • 69 out of 130 people had autism (53 percent)
  • 16 out of 130 people had ADHD (12 percent)
  • 20 out of 130 people had an anxiety disorder (15 percent)
53%
69 out of 130 people had autism.
12%
16 out of 130 people had ADHD.
15%
20 out of 130 people had an anxiety disorder.

Mobility

People who have SCN2A-related syndrome had impaired motor skills, and many people had low muscle tone.

  • 32 out of 81 children required a wheeled device for movement (40 percent)
  • 89 out of 130 people had low muscle tone (69 percent)

Where can I find support and resources?

FamilieSCN2A Foundation

The FamilieSCN2A Foundation’s mission is to accelerate research, build community, and advocate to improve the lives of ALL those affected by SRDs around the world.

FamilieSCN2A Community Discussion Group

SCN2A Asia Pacific

At SCN2A Australia, their mission is to improve the lives of individuals and families affected by SCN2A-related disorders.

SCN2A Europe

SCN2A Families UK

Simons Searchlight

Simons Searchlight is an online international research program, building an ever growing natural history database, biorepository, and resource network of over 175 rare genetic neurodevelopmental disorders. By joining their community and sharing your experiences, you contribute to a growing database used by scientists worldwide to advance the understanding of your genetic condition. Through online surveys and optional blood sample collection, they gather valuable information to improve lives and drive scientific progress. Families like yours are the key to making meaningful progress. To register for Simons Searchlight, go to the Simons Searchlight website at www.simonssearchlight.org and click “Join Us.”

Sources and References

  • Ogiwara I. et al. Neurology, 73, 1046-1053, (2009). De novo mutations of voltage-gated sodium channel alphaII gene SCN2A in intractable epilepsies ncbi.nlm.nih.gov/pubmed/19786696
  • Liao Y. et al. Brain, 133, 1403-1414, (2010). Molecular correlates of age-dependent seizures in an inherited neonatal-infantile epilepsy ncbi.nlm.nih.gov/pubmed/20371507
  • Liao Y. et al. Neurology, 75, 1454-1458, (2010). SCN2A mutation associated with neonatal epilepsy, late- onset episodic ataxia, myoclonus, and pain ncbi.nlm.nih.gov/pubmed/20956790
  • Howell KB. et al. Neurology, 85, 958-966, (2015). SCN2A encephalopathy: A major cause of epilepsy of infancy with migrating focal seizures ncbi.nlm.nih.gov/pubmed/26291284
  • Leach EL. et al. European Journal of Paediatric Neurology, 20, 772-776, (2016). Episodic ataxia associated with a de novo SCN2A mutation ncbi.nlm.nih.gov/pubmed/27328862
  • Ben-Shalom R. et al. Biological Psychiatry, 82, 224-232, (2017). Opposing effects on NaV1.2 function underlie differences between SCN2A variants observed in individuals with autism spectrum disorder or infantile seizures ncbi.nlm.nih.gov/pubmed/28256214
  • Foster LA. et al. Pediatric Neurology, 66, 108-111, (2017). Infantile epileptic encephalopathy associated with SCN2A mutation responsive to oral mexiletine ncbi.nlm.nih.gov/pubmed/27867041
  • Wolff M. et al. Brain, 140, 1316-1336, (2017). Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders ncbi.nlm.nih.gov/pubmed/28379373
  • Berecki, G., Howell, K. B., Heighway, J., Olivier, N., Rodda, J., Overmars, I., Vlaskamp, D. R. M., Ware, T. L., Ardern-Holmes, S., … Petrou, S. (2022). Functional correlates of clinical phenotype and severity in recurrent SCN2A variants. Communications Biology, 5(1), 515. https://pubmed.ncbi.nlm.nih.gov/35637276/
  • Berg, A. T., Thompson, C. H., Myers, L. S., Anderson, E., Evans, L., Kaiser, A. J. E., Paltell, K., Nili, A. N., DeKeyser, J. M., … George, A. L., Jr. (2024). Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders. Brain, awae125. https://pubmed.ncbi.nlm.nih.gov/38651838/
  • Berg, A. T., Thompson, C. H., Myers, L. S., Anderson, E., Evans, L., Kaiser, A. J. E., Paltell, K., Nili, A. N., DeKeyser, J. M., … George, A. L., Jr (2024). Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders. Brain : a journal of neurology, awae125. Advance online publication. https://doi.org/10.1093/brain/awae125
  • Simons Searchlight registry update April 2024. https://cdn.simonssearchlight.org/wp-content/uploads/2024/04/16044447/SCN2A-23Q4-24Q1.pdf
  • Zeng, Q., Yang, Y., Duan, J., Niu, X., Chen, Y., Wang, D., Zhang, J., Chen, J., Yang, X., … Zhang, Y. (2022). SCN2A-related epilepsy: The phenotypic spectrum, treatment and prognosis. Frontiers in Molecular Neuroscience, 15, 809951. https://pubmed.ncbi.nlm.nih.gov/35431799/