SCN2A-Related Disorders

Pathogenic variants (“mutations”) in the SCN2A gene cause a range of neurological conditions, including severe early-onset epilepsies, autism spectrum disorder and movement disorders. Some individuals with SCN2A-related disorders have milder presentations that are typically referred to as self-limited (benign) neonatal/infantile epilepsies that may run in families. The symptoms a child experiences and the severity of the disorder can vary widely and will depend on the particular SCN2A-related disorder the child has.

SCN2A is not the name of a medical condition but is rather the name of the gene that is affected. When a disorder is traced back to a disease-causing (pathogenic) variant in the SCN2A gene, it is called an SCN2A-related disorder.

SCN2A-related disorders fall into two broad categories, although some children have presentations that overlap between these categories:

• SCN2A-developmental and epileptic encephalopathy
• Self-limited neonatal/infantile epilepsy

Seizures beginning in infancy, not associated with a fever, may be the first indication of an SCN2A-related disorder. Seizures from some SCN2A-related disorders may begin in the first year of life and even within days of birth. However, seizures in SCN2A-related disorders may also begin later in childhood.

SCN2A-Developmental and Epileptic Encephalopathy

Encephalopathy refers to a disease that affects the functioning of the brain. Children with SCN2A-developmental and epileptic encephalopathy often experience seizures that start early in infancy, sometimes even shortly after birth. These seizures may be difficult to control with anti-seizure medications. Children with SCN2A-developmental and epileptic encephalopathy often have delays in reaching developmental milestones and may have several types of seizures during their disease course.

Some children with SCN2A-developmental and epileptic encephalopathy also have:

• Poor muscle tone (hypotonia)
• Movement disorders
• Behavior disorders, including features of autism spectrum disorder
• Feeding difficulties
• Difficulties with vision, also referred to as cortical visual impairment (CVI)

In some cases, intellectual disability or the behaviors associated with autism spectrum disorder are the first symptoms of SCN2A-development and epileptic encephalopathy, and seizures may appear later in childhood. Some children with SCN2A-developmental and epileptic encephalopathy never develop epilepsy. For children without epilepsy or with later-onset epilepsy, healthcare professionals may also use the term SCN2A-related autism or SCN2A-related neurodevelopmental disorders.

Self-limited Neonatal/Infantile Epilepsy

Self-limited neonatal/infantile epilepsy (formerly called benign familial neonatal/infantile seizures) is a rare form of SCN2A-related disorders that is less severe than SCN2A-developmental and epileptic encephalopathy. This type of SCN2A-related disorder is characterized by seizures that begin early in infancy in an otherwise well neonate or infant. Often there is a positive family history of seizures in infancy in a parent or other family member. Seizures usually respond well to anti-seizure medications and often stop by age 2. Developmental milestones are typically achieved on time, and long-term development and cognition are not affected. Seizures are called “self-limited” because they usually will resolve on their own with no need for ongoing anti-seizure medications.

Seizures that begin shortly after birth or in infancy and are not associated with fever may suggest an SCN2A-related disorder. A positive family history of seizures may suggest a diagnosis of a milder familial SCN2A-related epilepsy. Symptoms of intellectual disability or autism spectrum disorder may also suggest an SCN2A-developmental and epileptic encephalopathy, which may lead to seizures later in childhood.

Genetic testing is required to confirm a diagnosis.

Additional tests may also be done, including:

• Electroencephalogram (EEG) to look for evidence of abnormal brain activity and seizures
• Magnetic resonance imaging (MRI) to look for structural brain abnormalities

Many children with SCN2A-developmental and epileptic encephalopathy are also diagnosed with specific epilepsy syndromes based on the types of seizures they have experienced and features of their EEG.

Some of these epilepsy syndromes include:

• Ohtahara syndrome
• Epilepsy of infancy with migrating focal seizures
• West syndrome
• Lennox-Gastaut syndrome

In these cases, the epilepsy syndrome diagnosis is a description of the types of seizures the child is having, but the genetic diagnosis of SCN2A-developmental and epileptic encephalopathy is the primary diagnosis that explains why a child has developed epilepsy.

All children with SCN2A-related disorders have a pathogenic variant (“mutation”) in the gene SCN2A, which encodes the instructions to make a protein in the brain called a sodium channel. Pathogenic variants that affect the SCN2A sodium channel impair the flow of sodium ions in the brain.

SCN2A-Developmental and Epileptic Encephalopathy

In children with SCN2A-development and epileptic encephalopathy, the pathogenic variant may affect the SCN2A sodium channel in different ways. In some cases, the SCN2A mutation leads to overactivity of the ion channel; in other cases, the mutation leads to decreased activity of the ion channel. Changes in the flow of sodium ions in the brain causes epilepsy and associated developmental differences.
In most children with SCN2A-development and epileptic encephalopathy, the pathogenic SCN2A variant occurred spontaneously (de novo) and was not inherited from either parent. In rare cases, the pathogenic SCN2A variant has been passed on from an asymptomatic parent due to parental mosaicism. Just like a mosaic piece of art, in which each tile is different, a mosaic parent has distinct cell types. Most cells of a mosaic parent do not carry the pathogenic SCN2A variant. However, a small proportion of cells do carry the pathogenic SCN2A variant in very low levels that may be difficult or impossible to detect.

Self-Limited Neonatal/Infantile Epilepsy

In children with self-limited neonatal/infantile epilepsy due to a pathogenic SCN2A variant, the flow of sodium ions in the brain is disrupted, but likely to a lesser extent than in children with SCN2A-development and epileptic encephalopathy. This difference likely explains why these children have less severe disorders than children with SCN2A-development and epileptic encephalopathy.

In most children with self-limited neonatal/infantile epilepsy, the pathogenic SCN2A variant was inherited from a parent who also had seizures as an infant.

Treatment for SCN2A-related disorders will depend on the type and severity of the seizures.

• A combination of seizure medications is typically used to control the different seizure types. Sodium channel blocking medications may be effective, especially for children whose seizures begin in the first three months of life.
• A different set of medications known as “rescue medications,” may be given to help stop or shorten clusters of seizures when they occur.
• Implantable devices such as vagus nerve stimulation (VNS) or responsive neurostimulation (RNS) may be considered when medications are not effective in controlling seizures.
• Dietary therapy, such as the ketogenic diet, may be helpful in some cases.

Family training and support is a key element in a successful epilepsy treatment plan. Parents and caregivers must know how to watch for and respond to seizures.
Cognitive and developmental delays or autism spectrum disorder associated with SCN2A-development and epileptic encephalopathy are treated with physical, occupational,and speech therapy, and with the support of early intervention services. Care may be provided by a developmental pediatrician.

Families come to our Epilepsy Neurogenetics Initiative (ENGIN) Clinic from all over the world. Children with SCN2A-related disorders who are cared for at CHOP will receive cutting-edge genetic testing to confirm the underlying cause of their condition, as well as parental testing to confirm the diagnosis and inform recurrence risk with a subsequent pregnancy. Through ENGIN, your child will have access to any other medical specialists they may need. They will also have access to a full range of epilepsy therapies provided through CHOP’s Pediatric Epilepsy Program, including epilepsy management, dietary treatment and epilepsy surgery, cutting edge research and clinical trials, and ongoing follow-up care.

All individuals seen in the ENGIN Clinic are offered the opportunity to participate in research studies. ENGIN providers are collaborators on the NIH-funded Channelopathy-Associated Epilepsy Research Center, the goal of which is to understand how variation in ion channel genes including SCN2A leads to epilepsy and to advance the development of novel therapeutics.

The Epilepsy Neurogenetics Initiative (ENGIN) at Children’s Hospital of Philadelphia integrates genetic testing into the diagnosis and treatment of children with difficult-to-treat or unexplained epilepsies, genetic epilepsy syndromes, and other genetic neurodevelopmental disorders. We combine cutting-edge clinical care and advanced genetic testing with innovative research to identify the underlying cause of a child’s epilepsy and develop an individualized approach to treatment and management.

• FamilieSCN2A Foundation
• Simons SearchLight
• Beyond the Ion Channel | Dr. Helbig’s Blog for The ILAE Genetics Commission