Highlighting SCN2A on its awareness day

February 24 is SCN2A Awareness Day, and it’s a prime opportunity to spotlight the SCN2A gene, infamous for its association with a spectrum of neurodevelopmental disorders, such as epilepsy and autism.

SCN2A encodes the neuronal voltage-gated sodium channel (VGSC) NaV1.2, which is widely expressed throughout the central nervous system but not in peripheral tissues. More specifically, NaV1.2 predominantly localizes in excitatory, glutamatergic neurons, where it coexists with another VGSC, NaV1.6 (SCN8A). Inhibitory interneurons, however, largely express NaV1.1 (SCN1A), not NaV1.2, except in certain interneuron subclasses.

Interestingly, the ‘neonatal’ NaV1.2 splice isoform is less excitable than the ‘adult’ isoform, reducing neuronal excitability during early brain development. In addition, the subcellular distribution of NaV1.2 changes markedly over development. During early development and in infancy, NaV1.2 functions as the primary sodium channel for initiating and propagating action potentials. Later on, NaV1.6 largely replaces NaV1.2 in the distal axon initial segment (AIS), taking over the role of the main channel for action potential initiation. In mature neurons, NaV1.2 expression is limited to the proximal AIS region, right next to the soma. It is believed that such NaV1.2 localization helps action potentials backpropagate to the soma, influencing many neuronal functions, such as synaptic plasticity or gene transcription.

Given how important NaV1.2 is for the initiation and propagation of action potentials, particularly at the early stages of life, dysfunction of this channel is associated with several devastating neurodevelopmental disorders, including infantile epileptic encephalopathy, benign familial infantile seizures, and autism spectrum disorder/intellectual disability. Some studies also report associations with Dravet syndrome, schizophrenia, as well as familial and sporadic hemiplegic migraine. In general, gain-of-function variants lead to epilepsy and seizures, while loss-of-function variants are associated with autism and intellectual disability.

Currently, two companies are actively developing treatments for SCN2A-related disorders. Praxis Precision Medicines now has three candidates in clinical development for the treatment of developmental and focal onset epilepsy: PRAX-222 (antisense oligonucleotide), PRAX-562 (persistent current blocker), and PRAX-628 (sodium current blocker). Also, Newron Pharmaceuticals is developing Evenamide (a non-selective VGSC blocker) for the treatment of schizophrenia.

Also, it’s essential to acknowledge the families, nonprofits, and charities, that tirelessly work to improve the lives of those affected by SCN2A-related disorders and push forward toward a cure. To support their efforts today, please consider visiting their websites (see below).

SCN2A Awareness and Research Organizations:

The FamilieSCN2A Foundation – https://www.scn2a.org/

SCN2A Europe – https://www.scn2a.eu/

SCN2A Asia Pacific – https://scn2aaustralia.org/

SCN2A Brasil – SCN2A Brasil