SCN3A-Related Neurodevelopmental Disorders

What are SCN3A-related neurodevelopmental disorders?

Pathogenic variants (“mutations”) in the SCN3A gene cause a spectrum of neurological conditions that are collectively called SCN3A-related neurodevelopmental disorders. The spectrum of SCN3A-related neurodevelopmental disorders includes epilepsy that is typically severe and very early onset, as well as developmental brain malformations (such as polymicrogyria) in many affected individuals. Some individuals with SCN3A-realted neurodevelopmental disorders have milder presentations including focal epilepsy with or without brain malformations. Most affected children have developmental delays that range from mild to profound.

SCN3A is not the name of a medical condition but is rather the name of the gene that is affected. The SCN3A gene encodes the instructions to form a sodium (abbreviated “Na+”) channel. Na+ channels are protein complexes that allow the positively-charged Na+ ion into cells including brain cells (neurons), leading to neuron activation.

Signs and symptoms of SCN3A-related neurodevelopmental disorders

SCN3A-Related Neurodevelopmental Disorders includes a spectrum of phenotypes. On the milder end of the spectrum, children may present with mild developmental delay/intellectual disability with speech/language delay with or without epilepsy. On the more severe end of the spectrum, children may present with early infantile epileptic encephalopathy/developmental and epileptic encephalopathy with or without multifocal or diffuse malformation of cortical development.

Seizures may improve outside of early childhood but seem to not resolve completely in more severe cases.
Phenotypes with treatment-resistant/intractable epilepsy are associated with early infantile epileptic encephalopathy.
A subset of patients exhibit dyskinetic movements, including dystonia, choreoathetosis and/or non-epileptic myoclonus.
A subset of patients exhibit non-epileptic dysautonomia or other autonomic disturbances, including episodic skin flushing involving one or both sides of the body.

SCN3A-related neurodevelopmental disorders can include the following clinical presentations:

Early infantile epileptic encephalopathy (also referred to as developmental and epileptic encephalopathy), with onset of seizures, often with multiple seizure types, before 1 year of age, abnormal electroencephalogram (EEG), and developmental delay, arrest and/or regression.
Malformation of cortical development (MCD), including polymicrogyria (PMG), pachygyria, or other dysgyria, or partial subcortical band heterotopia or lissencephaly. MCD can be diffuse, multifocal, bilateral perisylvian or focal.
Mild focal epilepsy, with or without MCD, and variable developmental delays ranging from isolated speech delay to mild-moderate developmental delay.

Diagnosis of SCN3A-Related Neurodevelopmental Disorders

Seizures beginning in the first days or weeks of life combined with diffuse developmental brain malformations (such as polymicrogyria) may suggest a diagnosis of an SCN3A-related neurodevelopmental disorder. However, the spectrum of clinical presentations is broad, and clinical features alone cannot be used to establish the diagnosis. Genetic testing is required to confirm the diagnosis of SCN3A-related neurodevelopmental disorders.

It is important to establish the extent of neurological involvement in SCN3A-related neurodevelopmental disorders via the following:

Pregnancy/prenatal history and birth history
Neurological examination
Physical examination
Electroencephalogram (EEG), including continuous video EEG for differential diagnosis of events of unclear nature that are often seen in SCN3A-related neurodevelopmental disorders, such as autonomic manifestations and myoclonus
Magnetic resonance imaging (MRI) of the brain to evaluate for developmental differences in brain structure.
Evaluation by a physical and occupational therapist

Genetics of SCN3A-Related Neurodevelopmental Disorders

All children with SCN3A-related neurodevelopmental disorders have a pathogenic variant (“mutation”) in the SCN3A gene, which encodes the instructions to make a protein in the brain called a sodium channel. The pathogenic variant may affect the SCN3A sodium channel in different ways. In many cases, the SCN3A mutation leads to overactivity of the sodium channel; in other cases, the mutation leads to deceased activity of the sodium channel. Changes in the flow of sodium ions into neurons in the brain cause epilepsy and associated neurodevelopmental differences.

In most children with SCN3A-related neurodevelopmental disorders, the pathogenic SCN3A variant occurred spontaneously (de novo) and was not inherited from either parent. In some cases, the pathogenic SCN3A variant has been inherited from a parent who also has a history of seizures or brain abnormalities. A family history of epilepsy may suggest an inherited SCN3A variant.

Treatment for SCN3A-Related Neurodevelopmental Disorders

A combination of anti-seizure drugs is typically used to control the different seizure types in SCN3A-related neurodevelopmental disorders. The type of medication often depends on the specific type of seizures. No specific anti-seizure medications have been shown to be more efficacious than another.

Why choose CHOP for treatment of SCN3A-related neurodevelopmental disorder?

Families come to our ENGIN clinic from all over the world. Through ENGIN, your child will have access to all the medical specialists they may need. They will also have access to the full range of epilepsy therapies provided through CHOP’s Pediatric Epilepsy Program, including medication, dietary treatment and epilepsy surgery, as needed, and ongoing follow-up care.

ENGIN team members were involved in the initial characterization of SCN3A-related neurodevelopmental disorder and are leading ongoing efforts to develop new treatments for the condition. Opportunities exist for enrollment in research studies.

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SCN3A-Related Neurodevelopmental Disorders