sarah pham

Epilepsy 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.

Specifi cally, mutations in genes encoding voltage-gated sodium channels contribute widely to a variety of genetic epilepsy syndromes. The scientifi c community has identifi ed 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 affi rms its mark as an area of major genetic epilepsy research. However, some members of the scientifi c 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 fl ow 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

regulators of electrical excitability. SCN1A and SCN3A differ in the types of voltage-gated Na+ channel � subunits Nav 1.1 and Nav 1.3, respectively.4 Nearly all patients with mutations in the SCN3A gene develop a “gain-of-function (GoF)” in Na+ channels that emerges in developing neurons and lead to an expression of over-excited neurons.4 These particular GoF properties describe mechanisms in which the Na+ channel opens too soon, closes too slowly, and leaves a trail of excess Na+ current that remains from the initial infl ux of Na+ that depolarizes (increase in membrane potential during an action potential) of the neurons.

Malformations in the cortical region of the brain may be considered one of the more surprising phenotypes in patients with the SCN3A variant. In fact, over 75% of patients (15/19 individuals) developed a type of brain malformation called perisylvian polymicrogyria (PMG).5 PMG refers to a condition characterized by abnormal development of the brain before birth in which there are excessive small folds.2 Common symptoms include seizures, learning disabilities, behavioral concerns, motor delay, and more.2 Differing from the other genes encoding ion-channels, SCN3A is the only ion channel with a phenotype of brain malformation in a majority of individuals with the SCN3A variant.5

In SCN3A-related developmental disorder, pathogenic variants cluster in transmembrane segments 4 to 6 of domains II to IV.5 These variants occur in regions of the Na+ channel called the “poreforming” regions that are crucial for the dynamic structure changes during opening and closing. As you can imagine, issues with the infl ux and effl ux of Na+ ions would disrupt the electrical and chemical communication of neurons, exacerbating uncontrolled excitability.

Conclusion

SCN3A-related developmental disorders continue to be extensively studied as a novel area of genetic epilepsy research. The distinct trait phenotypes linked to SCN3A gene mutation prompts researchers to delve into this particular subfi eld of study surrounded by obscurity. In elucidating the particular mechanisms of the SCN3A gene mutation, the scientifi c community may soon generate innovative therapies for epilepsy and other developmental disorders.

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