FEATURES Introduction
E
pilepsy is one of the most common neurological conditions that arise from a combination of acquired and genetic factors. Seizure syndromes are representative of different genetic mechanisms in epilepsy that may include issues with electrical signaling, proper positioning of neurons within the layers of the brain’s cortex, and developmental abnormalities among others.1 Describing an even more distinct subset of this neurological disorder, genetic epilepsy arises from single-gene mutations or structural changes in chromosomal DNA sequence. Specifically, mutations in genes encoding voltage-gated sodium channels contribute widely to a variety of genetic epilepsy syndromes. The scientific community has identified a vast majority of these mutations existing in a gene called “SCN1A.” Mutations in SCN1A lead to an expression of overlapping phenotypes such as in: Dravet syndrome, a severe myoclonic epilepsy of infancy also known as SMEI, intractable childhood epilepsy with generalized tonic clonic seizures (ICEGTC), and generalized epilepsy with febrile seizures plus (GEFS+).1 If even one copy of the SCN1A gene is passed down from parent to offspring, these genetic epilepsy phenotypes will appear. For this reason, the SCN1A gene affirms its mark as an area of major genetic epilepsy research. However, some members of the scientific community have branched off to identify other possible pathogenic, or causative, variants. Novel research pinpoints mutations in the “SCN3A” gene
that give rise to an intriguing overlap of features in SCN3A patients including epilepsy, brain (cortical) malformation, and intellectual or developmental disorder.
The SCN3A Gene The SCN3A gene is highly expressed in the embryonic brain during the fetal gestational weeks (WKSG) and gradually decrease postnatally (after birth).4 As you can imagine, elucidating the pathogenic mechanisms of this gene would require meticulous study of the developing neuron due to the narrow time-span of SCN3A’s peak expression levels. De novo mutations are new genetic changes (not passed down from parents) caused by mutagenesis during the formation of male and female gametes. De novo mutations represent the most extreme form of rare genetic variation as they tend to have more deleterious effects compared to inherited variants and can be passed down to offspring as inherited mutations.3 Current research establishes De novo pathogenic variants in SCN3A as the cause of developmental and epileptic encephalopathy.5 Three unique aspects of SCN3A that make it worthwhile to study include: gain-of-function in sodium (Na+) channels, cortical malformations, and the unique spectrum of disease. Sodium (Na+) channels are primarily found in the brain and control the flow of Na+ ions into neurons. These voltage-gated Na+ channels mediate transfer of electrical signals between and among neurons called action potentials and serve as critical
Figure 1: Development of babies via germination, embryonic, and fetal stages. Spring 2022 | PENNSCIENCE JOURNAL 25
