| Summary: | Abstract Triadin-1, encoded by TRDN, is an important component of the calcium release unit (CRU) in the sarcoplasmic reticulum of cardiac myocytes, interacting both with ryanodine receptors and calsequestrin. This article reviews evidence substantiating a link between TRDN mutations and potentially fatal ventricular arrhythmias. Evidence from mouse TRDN knockout models indicates structural and functional changes to the cardiac myocyte CRU in the absence of triadin that result in disturbed Ca2+ handling and susceptibility to adrenergic agonist provoked arrhythmias. In particular, cellular electrophysiology experiments have provided evidence of reduced Ca2+ induced inactivation of L-type Ca2+ channels consequent to TRDN knockout. A number of reports since 2012 have identified patients with a CPVT phenotype, some of whom also exhibit prolonged QTc intervals, with TRDN mutations. Symptomatic patients have homozygous or compound heterozygous mutations predicted to result in absent or nonfunctional triadin. Typically they have experienced serious ventricular arrhythmias or cardiac arrest at a very young age against a background of exertion, excitement or stress. Some patients have also shown skeletal muscle weakness. β adrenoceptor blockers, particularly nadolol, have been used successfully in some patients, though others have continued to experience cardiac events. Implantable devices have been critically important in cardioverting episodes of ventricular fibrillation in a number of patients. Flecainide has been successful at reducing the burden on implantable devices in two patients. Potential future additional/alternative pharmacological treatments include L-type Ca2+ channel blockers, the class Ic antiarrhythmic propafenone and the β adrenoceptor blocker carvedilol. The potential value of such strategies should be explored using appropriate in vitro and in vivo models. In conclusion, triadin knockout syndrome is inherited in an autosomal recessive fashion and should be considered in cases of CPVT or Long QT Syndrome in which mutations to ion channels/transporters are not found. It should be particularly, though not exclusively, suspected in cases with concomitant muscle weakness. Further work is required to identify optimal therapeutic strategies.
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