Mutations in SCN2A are the most common cause of neurodevelopmental disease — however, at present there is no corrective therapy specifically for SCN2A patients. All current medications are focused primarily on symptomatic relief. Epilepsy and autism are the most prominent conditions but there are numerous comorbidities, including sensory dysfunction, movement/muscle disorders, intellectual disability, gastrointestinal complications, metabolic abnormalities and others. There is a considerable unmet need among SCN2A patients.
“Mutations in SCN2A are the most common cause of neurodevelopmental disease…”
SCN2A:
Evolution To a Critical Gene in Neurological Function
2004
Mutations in SCN2A were initially found in a predominately benign inherited form of epilepsy in a very small population which caused self remitting infantile seizures with a good long term prognosis for the patient.
2005-2010
What resulted was a limited focus on SCN2A within the academic and commercial communities, due to this initial characterization, nascent diagnostic capabilities, cost prohibitive commercial pathway based on limited population estimates, and isolated, inconsistent case reporting.
2011-2014
An increasing number of de novo mutations in SCN2A with a more severe disease presentation were being reported. As a result, SCN2A was also accepted as a severe cause of epilepsy.
2014-2016
As severe cases began to appear with more consistency throughout the world, RogCon, as well as a handful of researchers, began working more closely on studying SCN2A mutations. Still, there remained significant limitations on the understanding of the complexities of SCN2A pathology, precise biophysical consequences and how to effectively treat the symptoms of the emerging heterogeneous clinical presentations.
2016-Present
With improvements in diagnostic capabilities and the addition of SCN2A to most standard epilepsy panels, genetic diagnostic companies experience significant increase in SCN2A diagnoses, leading to SCN2A being recognized as the second most common epilepsy gene and the single biggest monogenic cause of autism. Increasing perception of this broadening roles made it arguably the single most critical gene for neurodevelopmental disorders. RogCon advances several programs to bring true disease-modifying treatments to SCN2A patients.
SCN2A is a brain sodium channel gene critical to life. Every action we take engages SCN2A (e.g., drinking a glass of water).
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You realize that you are parched. This realization comes from a signal sent from your body that travels to your brain via neurons.
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Your brain sends a signal to your arms (via neurons) to pick up the glass of water in front of you and start drinking.
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While drinking the water, your body sends a signal to your brain (via neurons), indicating that it has had enough to drink.
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Your brain sends a signal to your body (via neurons) to stop drinking and put the glass back down.
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The signals moving from body to brain and vis versa occur almost instantaneously and are occurring all day and night.
How this signaling works:
Neurons are bathed in an environment consisting of sodium ions (Na+) and potassium ions (K+). Opening and closing of sodium and potassium channels, proteins embedded in the neuron’s membrane acting as molecular gates, results in sodium and potassium flow and consequent electrical signaling (e.g., the signal from your brain telling your arm to pick up a glass of water).
SCN2A (Nav1.2) is a type of sodium channel called a “voltage-gated sodium channel”, and is expressed broadly in the CNS in excitatory neurons. Therefore, SCN2A plays a critical role in the brain’s ability to send and receive signals.
A mutation in SCN2A may cause a malfunction in the channel opening, the channel closing, the flow of ions across the channel and/or the period during which the cell returns to its resting state – any one of which will cause devastating consequences to the way in which the signal gets interpreted throughout the body.
Loss-of-Function (LoF) Mutations
- LoF mutations are mutations that result in reduced or abolished protein function.
- In the context of the SCN2A gene, LoF mutations lead to a reduction of activity of Nav1.2 proteins in the neurons.
- Loss of function mutations can be caused by missense (changing one amino acid for another) or nonsense (early termination of protein building, resulting in a shorter, defective protein) mechanisms.
Gain-of-Function (GoF) Mutations
- GoF mutations are mutations that result in a new protein function or a new pattern of protein distribution in the neuron.
- In the context of the SCN2A gene, GoF mutations lead to increased excitability of neurons due to overactive Nav1.2 proteins.
- GoF mutations are typically missense mutations.
Hundreds of pathogenic mutations in the SCN2A gene have been diagnosed. Each mutation can be classified as a Loss of Function (LoF) mutation, a Gain of Function (GoF) mutation, or show properties of both. A mutation is determined to be LoF or GoF by characterizing the electrophysiological profile of SCN2A. Several subpopulations within the SCN2A patient population exist. It is hypothesized that these subpopulations are strongly correlated with whether the mutation is LoF or GoF. Therapeutic choice appears to be dictated by whether the mutation is LoF or GoF.
The following seizure types are common in SCN2A patients. Some patients only experience one type of seizure, while others experience multiple types:
Tonic-clonic (grand mal)
What most people think of when they think of a seizure. Another word for this is a convulsion. The older term “grand mal” is no longer used.
Tonic
Muscle 'tone' is the muscle's normal tension at rest. In a tonic seizure, the tone is greatly increased: the body, arms, or legs become suddenly stiff or tense.
Myoclonic
Brief, shock-like jerks of a muscle or a group of muscles. Usually they don't last more than a second or two. There can be just one, but sometimes many will occur within a short time.
Atonic (drop attacks)
Muscle 'tone' is the muscle's normal tension. So in an atonic seizure, muscles suddenly become limp.
Absence (petit mal)
An absence seizure causes a short period of “blanking out” or staring into space. Like other kinds of seizures, they are caused by brief abnormal electrical activity in a person’s brain.
Infantile spasms
An epileptic spasm is a specific type of seizure seen in an epilepsy syndrome of infancy and childhood often called West Syndrome.
For detailed descriptions of each of the above seizure types, visit the Epilepsy Foundation.
The following movement/muscle disorders are present in many SCN2A patients:
Hypotonia
(Present in the majority of SCN2A patients) Hypotonia is a state of low muscle tone. Hypotonia can range from mild (reduced muscle strength) to severe (no control of neck muscles, inability to place weight on leg or shoulder muscles).
Ataxia
Ataxia is the loss of full control of bodily movements. Ataxia in SCN2A patients can occur periodically.
Dystonia
Dystonia is persistent or intermittent muscle contractions causing abnormal movements, postures, or both. Dystonia is usually patterned and twisting, in a way that often resembles a tremor.
Choreathetosis
Choreathetosis involuntary movements in a combination of chorea (irregular contractions) and athetosis (twisting or writhing).