What is SCN8A-Related Epilepsy?

Pathogenic variants (“mutations”) in the SCN8A gene cause a spectrum of neurological conditions, including epilepsy ranging in severity from mild to severe, developmental delays and cognitive impairment, autism spectrum disorder, and movement disorders with or without epilepsy. Some individuals with SCN8A-related epilepsy have milder epilepsy syndromes that may run in families, without associated cognitive delays. The symptoms a child experiences and the severity of the disorder can vary widely.

SCN8A is not the name of a medical condition but is rather the name of the gene that is affected. When epilepsy is traced back to a disease-causing (pathogenic) variant in the SCN8A gene, it is called SCN8A-related epilepsy.

Signs and symptoms of SCN8A-Related Epilepsy

In most children with SCN8A-related epilepsy, seizures, usually starting within in the first 18 months of life (with an average age of 4 months), are the first sign of the condition. However, seizures may also begin later in childhood. In some children, delays in achieving developmental milestones in infancy or early childhood may be the first indication of SCN8A-related epilepsy. The severity of epilepsy is highly variable. In some children, the seizures are easy to control with anti-seizure medications. In other children, the seizures may be more difficult to control and may require multiple anti-seizure medications. Most children with SCN8A-related epilepsies experience associated developmental and cognitive delays, ranging from mild to severe.

Children with SCN8A-related epilepsy may develop different types of seizures. Common seizure types may include:

• Focal clonic seizures (jerking movements of one part of the body)
• Generalized tonic-clonic seizures
• Infantile spasms
• Tonic (stiffening) seizures
• Absence seizures

Some children with SCN8A-related epilepsy also have:

• Decreased muscle tone (hypotonia)
• Movement disorders, particularly dystonia or choreoathetosis
• Behavior disorders, including features of autism spectrum disorder

Diagnosis of SCN8A-Related Epilepsy

Seizures beginning in infancy or early childhood may suggest an SCN8A-related epilepsy. A positive family history of seizures may suggest a diagnosis of a milder familial SCN8A-related epilepsy. Symptoms of intellectual disability, autism spectrum disorder or movement disorders may also suggest an SCN8A-related epilepsy. However, there are no typical signs and symptoms of SCN8A-related epilepsy that would allow us to make a diagnosis based on clinical features alone.

Genetic testing is required to confirm a diagnosis.

Additional testing 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.

Some children with SCN8A-related epilepsy 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:

• 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 SCN8A-related epilepsy is the primary diagnosis that explains why a child has developed epilepsy.

Genetics of SCN8A-related epilepsy

All children with SCN8A-related epilepsy have a pathogenic variant (“mutation”) in the gene SCN8A, which encodes the instructions to make a protein in the brain and peripheral nervous system called a sodium channel. The pathogenic variant may affect the SCN8A sodium channel in different ways. In many cases, the SCN8A mutation leads to overactivity of the sodium channel; in other cases, the mutation leads to decreased activity of the sodium channel. Changes in the flow of sodium ions in neurons in the brain cause epilepsy and associated neurodevelopmental differences.

In most children with SCN8A-related epilepsy, the pathogenic SCN8A variant occurred spontaneously (de novo) and was not inherited from either parent. In some cases, the pathogenic SCN8A variant has been inherited from a parent who also has a history of seizures. A family history of epilepsy may suggest an inherited SCN8A variant.
In rare cases, the pathogenic SCN8A 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 SCN8A variant. However, a small proportion of cells do carry the pathogenic SCN8A variant in very low levels that may be difficult or impossible to detect.

Treatment for SCN8A-Related Epilepsy

The goal of therapy is to decrease or eliminate seizures, improve cognitive function, and reduce risk of sudden unexpected death in epilepsy (SUDEP). Treatment for SCN8A-related epilepsy will depend on the type and severity of seizures.

• A combination of anti-seizure medications is typically used to control the different seizure types. Sodium channel blocking medications (including phenytoin, oxcarbazepine and lacosamide) may be effective.
• A different set of medications, known as “rescue therapies,” 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 SCN8A-related epilepsy are treated with physical, occupational and speech therapy, and with the support of early intervention services. Care may be provided by a developmental pediatrician.

ENGIN Clinic providers have been involved in the early efforts toward “precision” therapy for SCN8A-related epilepsy and can guide a trial of targeted therapy for patients with the condition.

Why choose CHOP for diagnosis and management of SCN8A-related epilepsy?

Families come to our ENGIN clinic from all over the world. Through ENGIN, your child will have access to an attending physician and genetic counselor with training and expertise in epilepsy neurogenetics, as well as physical and occupational therapy and social work. Patients also have access to the full range of epilepsy therapies provided through CHOP’s Pediatric Epilepsy Program, including medical and dietary therapies, as well as evaluation for potential epilepsy surgery for neuromodulatory device implantation. We also coordinate evaluation by specialists outside of neurology related to complications of SCN8A-related disorders including cardiology, ophthalmology, etc.

Through ENGIN, your child and family will have access to genetic testing for confirmation of the diagnosis, as well as the pattern of inheritance to guide family planning and maximize risk reduction.

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 SCN8A leads to epilepsy and to advance the development of novel therapeutics.

Resources for SCN8A-related disorders

• Epilepsy Foundation
• Beyond the Ion Channel | Dr. Helbig’s Blog for The ILAE Genetics Commission
• The Cute Syndrome Foundation
• SCN8A Epilepsy | From Michael Hammer, Ph.D. | Includes a patient registry