Variant-specific therapy for long QT syndrome type 3

Abstract

Congenital long QT syndrome (LQTS) is an inherited cardiac arrhythmia syndrome characterized by a prolonged QT interval on the electrocardiogram. 1 Wehrens X.H. Vos M.A. Doevendans P.A. Wellens H.J. Novel insights in the congenital long QT syndrome. Ann Intern Med. 2002; 137: 981-992 Crossref PubMed Google Scholar Long QT syndrome type 3 (LQT3) is caused by gain-of-function variants in the SCN5A-encoded α-subunit of the voltage-gated cardiac sodium (Na+) channel Nav1.5. LQT3-linked SCN5A variants typically interfere with fast inactivation of the channel, which causes increased sustained inward Na+ current (INa) and prolongation of the cardiac action potential. 2 Bennett P.B. Yazawa K. Makita N. George Jr., A.L. Molecular mechanism for an inherited cardiac arrhythmia. Nature. 1995; 376: 683-685 Crossref PubMed Scopus (777) Google Scholar In addition, some variants such as p.D1790G can prolong the ventricular action potential in the absence of an LQT3 variant-induced sustained Na+ current. 3 Wehrens X.H. Abriel H. Cabo C. Benhorin J. Kass R.S. Arrhythmogenic mechanism of an LQT-3 mutation of the human heart Na(+) channel alpha-subunit: a computational analysis. Circulation. 2000; 102: 584-590 Crossref PubMed Google Scholar Regardless of the biophysical mechanism, the abnormal Na+ influx can lead to early afterdepolarizations, which in turn cause triggered activity and the development of potentially fatal “torsades de pointes (TdP)-like” polymorphic ventricular tachycardia. Functional characterization and identification of a therapeutic for a novel SCN5A-F1760C variant causing type 3 long QT syndrome refractory to all guideline-directed therapiesHeart RhythmPreviewPathogenic variants in the SCN5A-encoded Nav1.5 sodium channel cause type 3 long QT syndrome (LQT3). We present the case of an infant with severe LQT3 who was refractory to multiple pharmacologic therapies as well as bilateral stellate ganglionectomy. The patient’s novel variant, p.F1760C-SCN5A, involves a critical residue of the Nav1.5’s local anesthetic binding domain. Full-Text PDF