SCN2A Spectrum of Autism and Epilepsy
Changes, or variants, in the SCN2A gene can cause a wide variety of issues. Just as each human is a unique individual, so is each genetic variant.
SCN2A-related disorders (SRDs) are often referred to as being on a spectrum because different variants affect individuals in different ways. Some variants make brain cells too active, causing seizures, while others slow down brain signals, leading to movement and/or learning problems. Variants in SCN2A can disrupt the delicate balance of brain signaling, leading to neurodevelopmental disorders, including epilepsy and autism spectrum disorder (ASD), with or without epilepsy.
The way SRDs present may include one or more of the following:
Epilepsy: Seizures that can start in the first few days or months of life. Some types of epilepsy linked to SCN2A may be hard to treat. In some cases, seizures stop by the age of two, in others they begin later in life.
Autism and Developmental Differences: Some people may have autism, learning delays, trouble with speech, or difficulties with movement.
Movement Problems: Some people have trouble with balance, coordination, or muscle control, making it hard to walk or use their hands.
What is SCN2A-Related Autism?
Variants (or changes) in the SCN2A gene are a leading single-gene cause of autism spectrum disorder. The gene gives instructions for making a part of brain cells called a sodium channel (also referred to as NaV1.2). These channels help brain cells send and receive tiny electrical signals which are very important for learning, memory, emotions, social skills, movement, and sensing the world.
Onset: Often identified in early childhood with delayed speech, poor social interaction, and repetitive behaviors.
Seizures: May be absent or appear later. In some cases, seizures are mild or well-controlled.
Cognition: Ranges from normal intelligence to moderate/severe intellectual disability (ID).
Motor issues: Hypotonia and motor delays are common.
Behavior: Can include hyperactivity, aggression, or sensory sensitivities.
Autism spectrum disorder (ASD) is a developmental disability caused by differences in the brain. —CDC
People with ASD may behave, communicate, interact, and learn in ways that are different from most other people. They often have problems with social communication and interaction, and restricted or repetitive behaviors or interests. People with ASD may also have different ways of learning, moving, or paying attention. These characteristics can make life very challenging. It is important to note that some people without ASD might also have some of these symptoms.
SCN2A-related autism is under-diagnosed
If you are reading this, you likely already have a genetic diagnosis indicating an SCN2A variant, but it is estimated that 75% of SCN2A cases are undiagnosed due to the delay in genetic testing for autism.
Whole exome/genome sequencing is key to identifying SCN2A variants in ASD. Early diagnosis can affect long term outcomes by providing targeted behavioral and educational interventions; monitoring for late-onset seizures or regression; and avoidance of medication that may worsen symptoms (e.g. sodium channel blockers in loss of function variants are contraindicated).
Often, the journey to the correct diagnosis is long. Parents who pushed to get genetic testing for their child with autism (or autism-like characteristics) often report that they "felt something else was going on" besides the classic presentation of autism. Learn more about their journeys in the Family Stories section.
What does Loss of Function Mean?
Loss of Function (LoF) refers to the effect of a particular genetic variant on the function of the gene, not the functional level of the person affected. It means that the gene does not produce a fully functional protein. Most autism-linked SCN2A variants are classified as loss-of-function.
The functional analysis of a particular variant is not something that shows up on a genetic test report. It is a complex process carried out in a research setting, however there are some clues to determining function. The age of seizure onset is one way (> 3 months means more likely loss-of or mixed function). The presence of a truncated (stopped) variant or deleted gene is another indication of loss-of-function.
It is important to consider the clinical presentation of symptoms along with any functional information when deciding on treatment options. A well-informed neurologist and genetic counselor will be able to give guidance. Please contact us if you need educational assistance.
What is SCN2A-Related Epilepsy?
Seizures and epilepsy are not the same. An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Epilepsy is a disease characterized by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological, and social consequences of this condition.
SCN2A-related epilepsy is caused by a change, or variant, in the SCN2A gene in an individual. A diagnosis of SCN2A-related epilepsy can only be made through genetic testing. Fortunately, it is becoming more common to do genetic testing when unexplained seizures occur, especially in infants and children.
There are many seizure disorders associated with SCN2A, such as Developmental and Epileptic Encephalopathy (DEE), Infantile Spasms (IS), and Self-limited familial neonatal-infantile epilepsy (SeLFNIe). The names and descriptions continue to evolve over time. It is important to understand that the etiology (cause) of seizures is SCN2A, even if the individual also has a known syndrome such as Lennox-Gastaut.
Note: A seizure is an event and epilepsy is the disease involving recurrent unprovoked seizures. SCN2A-related epilepsy occurs when a genetic test shows that a particular pathogenic (disease-causing) variant of the SCN2A gene is present in a person.
A person is considered to have epilepsy if they meet any of the following conditions:
At least two unprovoked (or reflex) seizures occurring greater than 24 hours apart.
One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years.
Diagnosis of an epilepsy syndrome. Epilepsy is considered to be resolved for individuals who had an age-dependent epilepsy syndrome but are now past the applicable age or those who have remained seizure-free for the last 10 years, with no seizure medicines for the last 5 years.
Content on Epilepsy is from The Epilepsy Foundation @ www.epilepsy.com
What does Gain of Function Mean?
In genetics, Gain of Function (GoF) refers to the effect of a particular change, or variant, on the function of the gene, not the functional level of the person affected. It means that the gene protein is being expressed inappropriately (i.e. the sodium channel is over-excited and lets too much sodium into the cell). Most early onset epilepsy-linked SCN2A variants are classified as gain-of-function.
The functional analysis of a particular variant is not something that shows up on a genetic test report. It is a complex process carried out in a research setting, however there are some clues to determining function. The age of seizure onset is one way: <3 months means more likely a gain of function).
It is important to consider the clinical presentation of symptoms along with any functional information when deciding on treatment options. A well-informed neurologist and genetic counselor will be able to give guidance. Please contact us if you need educational assistance.
What does Mixed Function Mean?
When talking about SCN2A variants, "mixed function" generally refers to a variant that has a combined effect on the gene, rather than a purely loss-of-function or gain-of-function effect.
The functional analysis of a particular variant is not something that shows up on a genetic test report. It is a complex process carried out in a research setting, however there are some clues to determining function. It is important to consider the clinical presentation of symptoms along with any functional information when deciding on treatment options. A well-informed neurologist and genetic counselor will be able to give guidance. Please contact us if you need educational assistance.