The SCN1A gene variants and epileptic encephalopathies

Abstract

The voltage-gated sodium channels are fundamental units that evoke the action potential in excitable cells such as neurons. These channels are integral membrane proteins typically consisting of one α-subunit, which forms the larger central pore of the channel, and two smaller auxiliary β-subunits, which modulate the channel functions. Genetic alterations in the SCN1A gene coding for the α-subunit of the neuronal voltage-gated sodium ion channel, type 1 (NaV 1.1), is associated with a spectrum of seizure-related disorders in human, ranging from a relatively milder form of febrile seizures to a more severe epileptic condition known as the Dravet syndrome. Among the epilepsy genes, the SCN1A gene perhaps known to have the largest number of disease-associated alleles. Here we present a meta-analysis on the SCN1A gene variants and provide comprehensive information on epilepsy-associated gene variants, their frequency, the predicted effect on the protein, the ethnicity of the affected along with the inheritance pattern and the associated epileptic phenotype. We also summarize our current understanding on the pathophysiology of the SCN1A gene defects, disease mechanism, genetic modifiers and their clinical and diagnostic relevance.

Genetic Variants Identified from Epilepsy of Unknown Etiology in Chinese Children by Targeted Exome Sequencing

“…Our findings also support that the genetic susceptibility for epilepsy is shared among different races. While the clinical presentations for these patients carrying the recurrent mutations are similar to the Caucasian children based on the review of the data available in the reports1415162627. It would be interesting in future study to compare them systematically in parallel with larger sample size and determine whether a significant modifier effect may be present in different genetic background.…”

“…These variants are either recurrent mutations or novel but deleterious variants in known epilepsy genes. We identified 2 recurrent mutations (c.311 C>T, p.Ala104Val and c.181 C>T, p.Leu61Phe) in SCN1A gene (http://www.ncbi.nlm.nih.gov/clinvar), a known epilepsy gene for Dravet syndrome (DS), generalized epilepsy with febrile seizures plus (GEFS+) and epileptic encephalopathy141516. In D1353 family, a de novo but recurrent mutation of c.311 C>T was found in a boy with Dravet syndrome, intractable seizure, significant regression of intellectual ability, and autistic behaviors.…”

Severe peri-ictal respiratory dysfunction is common in Dravet syndrome

“…In 70%-95% of cases, DS is due to mutations of SCN1A (32)(33)(34), which encodes the sodium channel Nav1.1. SUDEP is particularly common in patients with DS, causing death in 5%-10% of cases, most commonly during the first few years of life (31,35,36).…”

Myoclonic Seizures☆

“…Some myoclonic epilepsies, such as SMEI, have specific gene associations. SMEI is associated with SCN1A (Parihar and Ganesh, 2013).…”

“…Again, the seizures are generally more common upon awakening. They appear in the first four years of life and are associated with febrile seizures (Parihar and Ganesh, 2013). There is often a family history of seizures.…”