Phenotypic Overlap of Lethal Arrhythmias Associated with Cardiac Sodium Mutations: Individual-Specific or Mutation-Specific?
Mutations in cardiac sodium channel gene SCN5A are responsible for a spectrum of hereditary arrhythmias including type-3 long QT syndrome (LQT3), Brugada syndrome (BrS), conduction disturbance, and sinus node dysfunction. These syndromes were originally regarded as independent entities with distinct clinical manifestations and biophysical properties. However, recent evidence shows considerable clinical overlap among these disorders, implicating a new disease entity referred to as an overlap syndrome of cardiac sodium channelopathy. Class IC sodium channel blockers often induce BrS phenotype in some patients with LQT3. Furthermore, recent genetic studies have revealed that E1784K is the most prevalent SCN5A mutation responsible not only for LQT3 but BrS, confirming the clinical and genetic overlap of LQT3 and BrS. Here I show evidence that the clinical manifestations of SCN5A mutations are most probably determined by the biophysical and pharmacological properties of the mutations. I also provide an overview of current knowledge on the clinical features, prevalence, and molecular and biophysical mechanisms underlying the overlap syndrome to gain more insight into this complex issue and generate better therapeutic strategies for patient management.
KeywordsBrugada syndrome flecainide long QT syndrome overlap syndrome SCN5A
The author thanks the following investigators who were extensively involved in the international project “Functional characterization of the clinical overlap in cardiac sodium channelopathies”  for collecting clinical and genetic information on the LQT3 families, as well as the functional evaluation of the mutations: Elijah Behr (St George’s University of London, London, UK), Wataru Shimizu (National Cardiovascular Center, Suita, Japan), Shigetomo Fukuhara and Naoki Mochizuki (National Cardiovascular Center Research Institute, Suita, Japan), Minoru Horie (Shiga University of Medical Science, Otsu, Japan), Akihiko Sunami (International University of Health and Welfare, Ohtawara, Japan), Lia Crotti and Peter J. Schwartz (University of Pavia, Pavia, Italy), Eric Schulze-Bahr (University of Muenster, Munster, Germany), and Alfred L. George Jr. and Dan M. Roden (Vanderbilt University, Nashville, USA). The author also thanks to Saori Mine and Atsuko Iida for technical assistance.
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