Voltage-Gated Sodium Channel Dysfunctions in Neurological Disorders

Abstract

The pore-forming subunits (α subunits) of voltage-gated sodium channels (VGSC) are encoded in humans by a family of nine highly conserved genes. Among them, SCN1A, SCN2A, SCN3A, and SCN8A are primarily expressed in the central nervous system. The encoded proteins Nav1.1, Nav1.2, Nav1.3, and Nav1.6, respectively, are important players in the initiation and propagation of action potentials and in turn of the neural network activity. In the context of neurological diseases, mutations in the genes encoding Nav1.1, 1.2, 1.3 and 1.6 are responsible for many forms of genetic epilepsy and for Nav1.1 also of hemiplegic migraine. Several pharmacological therapeutic approaches targeting these channels are used or are under study. Mutations of genes encoding VGSCs are also involved in autism and in different types of even severe intellectual disability (ID). It is conceivable that in these conditions their dysfunction could indirectly cause a certain level of neurodegenerative processes; however, so far, these mechanisms have not been deeply investigated. Conversely, VGSCs seem to have a modulatory role in the most common neurodegenerative diseases such as Alzheimer’s, where SCN8A expression has been shown to be negatively correlated with disease severity.

Pathogenic SCN2A variants are associated with familial and sporadic hemiplegic migraine

“…Cooccurrence of infantile seizures and HM has been reported in families with CACNA1A [27,28], ATP1A2 [27], SCN1A [29]and PRRT2 mutations [7]. Like SCN2A, the sodium channel gene SCN1A was also known as an epilepsy gene before being identi ed as causing FHM3 [19]. Our results further strengthen the notion of shared mechanisms in migraine aura and epilepsy.…”

“…SCN2A, located on 2q24.3, encodes the neuronal voltage-gated sodium channel Na V 1.2, which is one of several sodium channels involved in initiation and propagation of action potentials in neurons. Na V 1.2 channels are expressed throughout the central nervous system with prominent expression in the cerebellar cortex [14,19]. SCN2A has been identi ed as the cause of multiple neurodevelopmental disorders including self-limited familial neonatal-infantile seizures (formally designated BFNIS) [20], early infantile and childhood onset epileptic encephalopathy [21], autism spectrum disorder and intellectual disability [14], encephalopathies associated with infantile movement disorders [22], self-limited infantile seizures with late-onset episodic ataxia [23,24], childhood-onset epileptic encephalopathy, and schizophrenia [19].…”

“…Na V 1.2 channels are expressed throughout the central nervous system with prominent expression in the cerebellar cortex [14,19]. SCN2A has been identi ed as the cause of multiple neurodevelopmental disorders including self-limited familial neonatal-infantile seizures (formally designated BFNIS) [20], early infantile and childhood onset epileptic encephalopathy [21], autism spectrum disorder and intellectual disability [14], encephalopathies associated with infantile movement disorders [22], self-limited infantile seizures with late-onset episodic ataxia [23,24], childhood-onset epileptic encephalopathy, and schizophrenia [19]. Our study shows that SCN2A variants can also cause pure hemiplegic migraine, as in all affected members of Family 1.…”

SCN1A—Characterization of the Gene’s Variants in the Polish Cohort of Patients with Dravet Syndrome: One Center Experience

“…Except for one patient (born at 27 Hbd), no significant complications of the perinatal period were observed. The patient born at 27 Hbd received a low Apgar score (3)(4)(5), required respiratory support and was diagnosed with RDS (respiratory distress syndrome), ROP (Retinopathy of Prematurity) and grade 1 IVH (Intraventricular Hemorrhage). Family history was burdened with the occurrence of febrile seizures in first-degree relatives in three patients and epilepsy in two.…”

“…Nav1.1 channels are predominantly found within GABA-ergic interneurons across many central nervous system (CNS) regions [3]. The inhibitory function of these interneurons contributes to maintaining a balance between excitation and inhibition in the CNS [4]. Disruption of this balance, in the case of SCN1A gene mutations, due to the restricted function of interneurons results in clinical symptoms that can manifest as both epileptic (a heterogeneous group of epileptic syndromes) and non-epileptic.…”