International Triadin Knockout Syndrome Registry

• Published in: Circulation. Genomic and precision medicine Vol. 12; no. 2; p. e002419
• Main Authors: Clemens, Daniel J, Tester, David J, Giudicessi, John R, Bos, J Martijn, Rohatgi, Ram K, Abrams, Dominic J, Balaji, Seshadri, Crotti, Lia, Faure, Julien, Napolitano, Carlo, Priori, Silvia G, Probst, Vincent, Rooryck-Thambo, Caroline, Roux-Buisson, Nathalie, Sacher, Frederic, Schwartz, Peter J, Silka, Michael J, Walsh, Mark A, Ackerman, Michael J
• Format: Journal Article
• Language: English
• Published: United States 01-02-2019
• Subjects: Adolescent; Adrenergic beta-Antagonists - therapeutic use; Arrhythmias, Cardiac - drug therapy; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - pathology; Carrier Proteins - genetics; Child; Child, Preschool; Defibrillators, Implantable; Electrocardiography; Exercise; Female; Heart Arrest - diagnosis; Heart Arrest - etiology; Humans; Male; Muscle Proteins - deficiency; Muscle Proteins - genetics; Registries; phenotype; genetics; long QT syndrome; human; pediatrics
• ISSN: 2574-8300
• DOI: 10.1161/circgen.118.002419

Triadin knockout syndrome (TKOS) is a rare, inherited arrhythmia syndrome caused by recessive null mutations in TRDN-encoded cardiac triadin. Based previously on 5 triadin null patients, TKOS has been characterized by extensive T-wave inversions, transient QT prolongation, and severe disease expression of exercise-induced cardiac arrest in early childhood refractory to conventional therapy.
We have established the International Triadin Knockout Syndrome Registry to include patients who have genetically proven homozygous/compound heterozygous TRDN null mutations. Clinical/genetic data were collected using an online survey generated through REDCap.
Currently, the International Triadin Knockout Syndrome Registry includes 21 patients (11 males, average age of 18 years) from 16 families. Twenty patients (95%) presented with either cardiac arrest (15, 71%) or syncope (5, 24%) at an average age of 3 years. Mild skeletal myopathy/proximal muscle weakness was noted in 6 (29%) patients. Of the 19 surviving patients, 16 (84%) exhibit T-wave inversions, and 10 (53%) have transient QT prolongation > 480 ms. Eight of 9 patients had ventricular ectopy on exercise stress testing. Thirteen (68%) patients have received implantable defibrillators. Despite various treatment strategies, 14 (74%) patients have had recurrent breakthrough cardiac events.
TKOS is a potentially lethal disease characterized by T-wave inversions in the precordial leads, transient QT prolongation in some, and recurrent ventricular arrhythmias at a young age despite aggressive treatment. Patients displaying this phenotype should undergo TRDN genetic testing as TKOS may be a cause for otherwise unexplained cardiac arrest in young children. As gene therapy advances, enrollment into the International Triadin Knockout Syndrome Registry is encouraged to better understand TKOS and to ready a well-characterized cohort for future TRDN gene therapy trials.