Inherited disorders of voltage-gated sodium channels

Abstract

A variety of inherited human disorders affecting skeletal muscle contraction, heart rhythm, and nervous system function have been traced to mutations in genes encoding voltage-gated sodium channels. Clinical severity among these conditions ranges from mild or even latent disease to life-threatening or incapacitating conditions. The sodium channelopathies were among the first recognized ion channel diseases and continue to attract widespread clinical and scientific interest. An expanding knowledge base has substantially advanced our understanding of structurefunction and genotype-phenotype relationships for voltage-gated sodium channels and provided new insights into the pathophysiological basis for common diseases such as cardiac arrhythmias and epilepsy. IntroductionVoltage-gated sodium channels (Na V Chs) are important for the generation and propagation of signals in electrically excitable tissues like muscle, the heart, and nerve. Activation of Na V Chs in these tissues causes the initial upstroke of the compound action potential, which in turn triggers other physiological events leading to muscular contraction and neuronal firing. Na V Chs are also important targets for local anesthetics, anticonvulsants, and antiarrhythmic agents.The essential nature of Na V Chs is emphasized by the existence of inherited disorders (sodium "channelopathies") caused by mutations in genes that encode these vital proteins. Nearly 20 disorders affecting skeletal muscle contraction, cardiac rhythm, or neuronal function and ranging in severity from mild or latent disease to life-threatening or incapacitating conditions have been linked to mutations in human Na V Ch genes (Table 1). Most sodium channelopathies are dominantly inherited, but some are transmitted by recessive inheritance or appear sporadic. Additionally, certain pharmacogenetic syndromes have been traced to variants in Na V Ch genes. The clinical manifestations of these disorders depend primarily on the expression pattern of the mutant gene at the tissue level and the biophysical character of Na V Ch dysfunction at the molecular level.This review will cover the current state of knowledge of human sodium channelopathies and illustrate important links among clinical, genetic, and pathophysiological features of the major syndromes with the corresponding biophysical properties of mutant Na V Chs. An initial brief overview of the structure and function of Na V Chs will provide essential background information needed to understand the nuances of these relationships. This will be followed by a review of the major syndromes, organized by affected tissue. Emphasis will be placed on relating clinical phenotypes to patterns of channel dysfunction that underlie pathophysiology of these conditions.

Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Nav1.1 Na+Channel Mutant

“…Mutations of Na v 1.1 (SCN1A) cause generalized epilepsy with febrile seizures plus (GEFSϩ) type 2, severe myoclonic epilepsy of infancy (SMEI), intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC), and simple febrile seizures (FS); mutations of Na v 1.2 (SCN2A) cause benign familial neonatal-infantile seizures (BFNIS) and benign familial infantile seizures (BFIS); mutations of ␤1 (SCN1B) cause GEFSϩ type 1 (Avanzini and Franceschetti, 2003;Scheffer and Berkovic, 2003;Noebels, 2003;George, 2005;Mantegazza et al, 2005a;Meisler and Kearney, 2005;Scalmani et al, 2006;Avanzini et al, 2007).…”

A case of appropriate inappropriate device therapy: Hyperkalemia-induced ventricular oversensing

“…Increases in extracellular [K + ] lead to a reduction in the electrochemical driving force for the outward movement of potassium ions, resulting in membrane depolarization and inactivation of cardiac voltage-gated sodium channels. Voltage-gated sodium channels are the key mediators of rapid myocardial conduction, and loss of their function produces functional conduction block (5). As such, when the serum potassium rises above 6.5 mM, there is slowing of phase 0 of the cardiac action potential and increased conduction delay, leading to widened QRS complexes and a prolonged PR interval.…”

Slamdance: seizing a fly model for epilepsy

“…A reduction in sodium channel conductance is associated with lowering both neuronal excitability and seizure susceptibility (George 2005;Segal and Douglas 1997). The lower I Nap /I Nat ratio observed in sda-treated larvae compared with seizure-prone sda larvae (Fig.…”

“…1A). I Nap has previously been shown to be relevant in human epilepsy, and is a potential target for drug therapies (George 2005;Segal and Douglas 1997). Hence, an effect of sda on this current component already suggests that this mutant is a potentially suitable fly model for epilepsy.…”

“…In early behavioral screens of Drosophila, Seymour Benzer (1971) noted that a number of mutant strains were transiently knocked out following mechanical stimulation, and these mutants were termed "bang-sensitive (b-s)". Genetic identification of several of these mutations revealed defective ion channels and synaptic machinery (George 2005;Song and Tanouye 2008) that likely induce seizures in the fly. Limited access to brain electrophysiology in the fly has prevented a better understanding of how these mutations lead to epileptiform activity (Glasscock and Tanouye 2005;Pavlidis et al 1994).…”