Daniel J Clemens1, David J Tester2, John R Giudicessi1, J Martijn Bos1, Ram K Rohatgi1, Dominic J Abrams2, Seshadri Balaji3, Lia Crotti4,5,6, Julien Faure7,8, Carlo Napolitano9,10, Silvia G Priori9,10, Vincent Probst11,12, Caroline Rooryck-Thambo13, Nathalie Roux-Buisson7,8, Frederic Sacher13, Peter J Schwartz4, Michael J Silka14, Mark A Walsh15, Michael J Ackerman1. 1. Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology and Experimental Therapeutics, Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, and Division of Heart Rhythm Services, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (D.J.C., D.J.T., J.R.G., J.M.B., R.K.R., M.J.A.). 2. Department of Cardiology, Boston Children's Hospital and Harvard Medical School, MA (D.J.A.). 3. Doernbecher Children's Hospital, Oregon Health and Science University, Portland (S.B.). 4. Center for Cardiac Arrhythmias of Genetic Origin & Laboratory of Cardiovascular Genetics, Istituto Auxologico Italiano, IRCCS, Milan (L.C., P.J.S.). 5. IRCCS Department of Cardiovascular, Neural & Metabolic Sciences, San Luca Hospital, Istituto Auxologico Italiano (L.C.). 6. Department of Medicine and Surgery University of Milano-Bicocca, Italy (L.C.). 7. Centre Hospitalier Universitaire de Grenoble Alpes (J.F., N.R.-B.). 8. Institut des Neurosciences de Grenoble, INSERM U1216, Grenoble, France (J.F., N.R.-B.). 9. Molecular Cardiology and Medicine Division, Istituti Clinici Scientifici Maugeri, IRCCS (C.N., S.G.P.). 10. Department of Molecular Medicine, University of Pavia, Italy (C.N., S.G.P.). 11. Reference Center for Rare Arrhythmic Disorders, Cardiologic Department, Nantes University Hospital, France (V.P.). 12. L'institut du thorax, INSERM 1087, Nantes, France (V.P.). 13. Electrophysiology and Heart Modeling Institute, Bordeaux University Hospital, IHU Liryc, University of Bordeaux, Pessac-Bordeaux, France (C.R.-T., F.S.). 14. Children's Hospital Los Angeles, University of Southern California (M.J.S.). 15. Paediatric Cardiology, University Hospital Bristol, United Kingdom (M.A.W.).
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Entities:
Keywords:
genetics; human; long QT syndrome; pediatrics; phenotype
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