The SCN2A gene – Structure and function
The sodium channel, voltage-gated, type II, alpha (SCN2A) gene is located on the positive strand of chromosome 2 (2q24.3) in humans.
SCN2A encodes the sodium channel NaV1.2 in neurons, which is one of four sodium channels in the central nervous system, along with NaV1.1 (SCN1A), NaV1.3 (SCN3A), and NaV1.6 (SCN8A), and relevant for the initiation and propagation of action potentials in neurons.
Sodium channels are protein structures containing a voltage-sensing domain which is sensitive to charge differences between the intracellular and extracellular sides of the membrane. This domain changes in form so that the channel is activated, permitting electrical conduction by way of sodium flux into the cell. Afterwards, an inactivation step will follow, so that the sodium channel is ready for the next activation.
Mutations
Mutations can be de novo
(i.e. non-inherited, one of the 70 mutations on average a newborn carries) or inherited from the parents – a genetic test can certify this. Mutations can be in different places of the SCN2A gene, and will have different impact – e.g. an alteration in a single amino acid in a protein can either have no impact on function or impair function or enhance function or create new effects; or the protein is just not produced. In any case, it can be determined whether the particular mutation brings a loss of function (Loss-of-Function or LoF – the sodium channel excitability is lowered, or the function is just destroyed) or a gain of function (Gain-of-Function or GoF – the sodium channel is more excitable due to the mutation). To have a more or less excitable sodium channel will have an impact on the treatment.
Frequency
It is predicted that more than 400 are to be born yearly in the USA alone, about 7.000 worldwide, but only very few are diagnosed. Once widespread genetic testing in (early) infantile epileptic encephalopathy (IEE), autism spectrum disorder (ASD) and intellectual disability (ID) is a reality, the frequency of known SCN2A cases will probably jump to hundreds per year, similar to the incidence of SCN1A-mediated Dravet syndrome (currently at 6.4 per 100 000 births). The incidence of Loss-of-Function (LoF) cases is expected to be approximately five times higher than Gain-of-Function (GoF) cases, although the number of known SCN2A cases is currently similar between GoF and LoF, certainly reflecting differences in the adoption of genetic testing, more frequent by early onset seizures.
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