Existing treatments – treating the symptoms
Seizures
Seizures often cannot be controlled with the use of antiepileptic drugs (AEDs). However, for children with early onset seizures (<3 months), sodium channel blockers like phenytoin and carbamazepine seem to be more effective.
For children with ASD/ID and seizures starting later (>12 months), nonsodium channel blockers like levetiracetam, benzodiazepines, and valproate seem to be the best option.
For seizures starting between 3 months and 12 months, standard AED guidelines are recommended, but the gain-of-function nature of these variants suggests sodium channel blockers would be more suitable.
Autism Spectrum Disorder (ASD), Attention Deficit Hyperactivity Disorder (ADHD), Intellectual Disability (ID)
For the time being, no SCN2A-specific recommendations can be made for the treatment of these symptoms. Therefore, standard management for children with these disorders should be followed.
Gastrointestinal disturbances
Many children have severe constipation, gastro-oesophageal reflux or diarrhoea. This could be because the gut is also controlled by its own nervous system which is affected by the mutation. The symptoms can be very severe, in which case they may be called gastrointestinal dysmotility. Children with severe problems can be referred to a paediatric gastroenterologist. They may recommend specific medications or procedures such as gastrostomy (feeding button insertion) or fundoplication (a procedure to tighten the junction between the gullet and the stomach to help severe reflux).
Movement disorders
Abnormal and rapid movements with flailing or writhing of the arms and legs (called dyskinesia or chorea) or holding an abnormal posture (dystonia) is frequent and can sometimes be mistaken for seizures. In fact these are involuntary movements or a movement disorder and there are specific treatments which may be prescribed by a paediatric neurologist.
Motor skills can be improved through specific physiotherapy.
Cortical Visual Impairment (CVI), sleep issues, urology problems, neuropathic pain, autonomic dysfunction, cerebral palsy
For the time being, no SCN2A-specific recommendations can be made for the treatment of these symptoms. Therefore, standard management for children with these disorders should be followed.
Future treatments – targeting the source
If the NaV1.2 channel function is restored to the ‘normal’ range, individuals with both gain and loss-of-Function could profit.
Small-molecule compounds
Drugs in form of small molecule compounds can be developed because ion channels such as NaV1.2 are good targets to either increase or decrease the function of the channel and therefore treat ASD/ID or IEE, respectively. However, side effects may be challenging, especially if the NaV1.2 channel activity is not regulated properly, which could result in IEE if overly enhanced or ASD/ID symptoms if overly decreased.
Advanced experimental tools are necessary to bring some light to these questions. First, transgenic mice help understand the general context. Beyond that, stem cells of patients can be used to produce neuronal cultures or even organoids (i.e. several neurons) where aspects like excitability or network behaviour with and without medication for specific SCN2A genetic variants can be tested.
Genetic edition
Some groups of researchers are working on genetic edition of mutated SCN2A genes, e.g. mainly using CRISPR-Cas9.
A research group has already managed to correct a SCN2A mutation through the injection of the gene-editing tool CRISPR into the brains of adolescent mice, which could mean that mutations in SCN2A may be treatable at any age.
It will still take some time (especially because genetic edition is not reversible) but results with mice are promising.
Text based on learnings from: Progress in Understanding and Treating
SCN2A-Mediated Disorders, Sanders, Stephan J. & Co.; Trends in Neurosciences, July 2018, Vol. 41, No. 7