The latter effect may form the basis for Ca<sup>2+</sup>-dependent Na<sup>+</sup> channel dysregulation in SCN4Achannelopathies associated with cold- and K<sup>+</sup>-aggravated myotonias.
Our findings broaden the spectrum of cardiac phenotypes associated with SCN5Achannelopathy, underlining the complex clinical manifestations of genetic variations within this gene.
The genetic test was positive in 12 (26%; 95% CI 15.6-40.3) patients; 10 (21.7%) had PKP2 mutation related to arrhythmogenic right ventricular dysplasia mutation, one (2.2%) KCNQ1 mutation and one (2.2%) SCN5A mutation related to channelopathies.
Impact statement The field of ion channelopathy caused by dysfunctional Nav1.5 due to SCN5A mutations is rapidly evolving as novel technologies of electrophysiology are introduced and our understanding of the mechanisms of various arrhythmias develops.
In this study, we investigated whether cardiac arrhythmias or channelopathies such as Brugada syndrome can be part of the clinical phenotype associated with SCN4A variants and whether patients with Brugada syndrome present with non-dystrophic myotonia or periodic paralysis and related gene mutations.
SCN5A mutations involving the α-subunit of the cardiac voltage-gated muscle sodium channel (NaV1.5) result in different cardiac channelopathies with an autosomal-dominant inheritance such as Brugada syndrome.
In 2 patients (1%), EMG studies demonstrated myotonia, and muscle biopsy showed mild myopathic features; 1 patient had myotonic dystrophy type 2, and the other had SCN4A-related muscle channelopathy.
This complex protein is encoded by the SCN5A gene that, in its mutated form, is implicated in various diseases, particularly channelopathies, specifically at cardiac tissue level.
In this report, for the first time, we associated the genetic variability of SCN4A with the development of essential tremor, which adds ET to the growing list of neurological channelopathies.
The relationship between two phenotypes and SCN4A has been confirmed with additional cases that remain extremely rare: severe neonatal episodic laryngospasm mimicking encephalopathy, which should be actively searched for since patients respond well to sodium channel blockers; congenital myasthenic syndromes, which have the particularity to be the first recessive Nav1.4 channelopathy.
Together, the results from this study demonstrate that the SCN5A(E558X/+) pig model accurately phenocopies many aspects of human cardiac sodium channelopathy, including conduction slowing and increased susceptibility to ventricular arrhythmias.
This large-animal model exhibits many phenotypes seen in patients with SCN5A loss-of-function mutations and has the potential to provide important insight into sodium channelopathies.
Mutations in the skeletal muscle channel (SCN4A), encoding the Nav1.4 voltage-gated sodium channel, are causative of a variety of muscle channelopathies, including non-dystrophic myotonias and periodic paralysis.
The notable pathophysiological overlap between familial SSS and Na channelopathy indicates that familial SSS with SCN5A mutations may represent a subset of cardiac Na channelopathy with strong male predominance and early clinical manifestations.
Hundreds of genetic variants in SCN5A, the gene coding for the pore-forming subunit of the cardiac sodium channel, Na(v) 1.5, have been described in patients with cardiac channelopathies as well as in individuals from control cohorts.
This observation confirms the possibility that SCN5A mutations may confer susceptibility for recurrent seizure activity, supporting the emerging concept of a genetically determined cardiocerebral channelopathy.
We report a Korean case of an overlap syndrome of cardiac sodium channelopathy with SCN5Ap.R1193Q polymorphism, treated by the placement of an intrapericardial implantable cardioverter-defibrillator (ICD) at the age of 27 months.