Keith A Dufendach1, Katherine Timothy2, Michael J Ackerman3, Benjamin Blevins4, Andreas Pflaumer5, Susan Etheridge2, James Perry6, Nico A Blom7, Joel Temple8, Devyani Chowdhury9, Jonathan R Skinner10, Christopher Johnsrude11, Andras Bratincsak12, J Martijn Bos3, Maully Shah13. 1. Department of Pediatrics, Division of Pediatric Cardiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Department of Pediatrics, Division of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 2. Department of Pediatrics, Division of Pediatric Cardiology, University of Utah, Salt Lake City, Utah. 3. Department of Cardiovascular Diseases, Division of Heart Rhythm Services, Mayo Clinic, Rochester, Minnesota; Department of Pediatrics, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota; Department of Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota. 4. Department of Pediatrics, Division of Pediatric Cardiology, Naval Medical Center San Diego, San Diego, California. 5. Department of Pediatrics, Division of Pediatric Cardiology, Royal Children's Hospital, MCRI, and University of Melbourne, Melbourne, Australia. 6. Department of Pediatrics, Division of Pediatric Cardiology, Rady Children's Hospital/UC San Diego, San Diego, California. 7. Department of Medicine, Division of Pediatric Cardiology, Leiden University Medical Center, Leiden, the Netherlands; Department of Medicine, Division of Pediatric Cardiology, Academic Medical Center, Amsterdam, the Netherlands. 8. Nemours/Alfred I. duPont Hospital for Children, Wilmington, Delaware. 9. Cardiology Care for Children, Lancaster, Pennsylvania. 10. Department of Pediatrics, Division of Pediatric Cardiology, Starship Children's Hospital, Auckland, New Zealand. 11. University of Louisville, Louisville, Kentucky. 12. Pediatric and Adult Congenital Cardiology, Kapi'olani Medical Specialists, Honolulu, Hawaii. 13. Department of Pediatrics, Division of Pediatric Cardiology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Electronic address: shahm@email.chop.edu.
Abstract
OBJECTIVES: The objective of this study was to evaluate contemporary clinical outcomes and identify triggers for arrhythmias or sudden death in an international cohort of Timothy Syndrome (TS) patients including those with novel TS-associated CACNA1C mutations. BACKGROUND: TS is an extremely rare genetic disorder of the L-type cardiac channel Cav1.2 encoded by CACNA1C. The syndrome is characterized by multisystem abnormalities consisting of QT prolongation, congenital heart defects, syndactyly, facial dysmorphism, and neurological symptoms. METHODS: Patients diagnosed with TS between January 1, 1994, and April 1, 2016, from 12 international tertiary care pediatric centers were included in this retrospective study. Data were gathered via survey from the patients' electrophysiologists. RESULTS: Seventeen patients diagnosed with TS were identified. Length of follow-up was 4.9 years (range 3.0 to 19.0 years). Mean QTc was 640 ms (range 500 to 976 ms). All patients were treated with beta-blockers; 13 patients (76%) were also treated with an implantable defibrillator. Eleven patients experienced an episode of aborted cardiac arrest, 6 associated with general anesthesia and 2 with hypoglycemia. Four patients died suddenly due to ventricular fibrillation, 2 of whom had associated hypoglycemia. CONCLUSIONS: This study shows that mortality in TS patients is due to multifactorial mechanisms, which include ventricular arrhythmias, pulseless electrical activity, and hypoglycemia. A simple nomenclature for ongoing studies of TS and related syndromes is described. A worldwide prospective registry is needed for continued exploration of this syndrome.
OBJECTIVES: The objective of this study was to evaluate contemporary clinical outcomes and identify triggers for arrhythmias or sudden death in an international cohort of Timothy Syndrome (TS) patients including those with novel TS-associated CACNA1C mutations. BACKGROUND: TS is an extremely rare genetic disorder of the L-type cardiac channel Cav1.2 encoded by CACNA1C. The syndrome is characterized by multisystem abnormalities consisting of QT prolongation, congenital heart defects, syndactyly, facial dysmorphism, and neurological symptoms. METHODS:Patients diagnosed with TS between January 1, 1994, and April 1, 2016, from 12 international tertiary care pediatric centers were included in this retrospective study. Data were gathered via survey from the patients' electrophysiologists. RESULTS: Seventeen patients diagnosed with TS were identified. Length of follow-up was 4.9 years (range 3.0 to 19.0 years). Mean QTc was 640 ms (range 500 to 976 ms). All patients were treated with beta-blockers; 13 patients (76%) were also treated with an implantable defibrillator. Eleven patients experienced an episode of aborted cardiac arrest, 6 associated with general anesthesia and 2 with hypoglycemia. Four patients died suddenly due to ventricular fibrillation, 2 of whom had associated hypoglycemia. CONCLUSIONS: This study shows that mortality in TS patients is due to multifactorial mechanisms, which include ventricular arrhythmias, pulseless electrical activity, and hypoglycemia. A simple nomenclature for ongoing studies of TS and related syndromes is described. A worldwide prospective registry is needed for continued exploration of this syndrome.
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Authors: Maully J Shah; Michael J Silka; Jennifer N Avari Silva; Seshadri Balaji; Cheyenne M Beach; Monica N Benjamin; Charles I Berul; Bryan Cannon; Frank Cecchin; Mitchell I Cohen; Aarti S Dalal; Brynn E Dechert; Anne Foster; Roman Gebauer; M Cecilia Gonzalez Corcia; Prince J Kannankeril; Peter P Karpawich; Jeffery J Kim; Mani Ram Krishna; Peter Kubuš; Martin J LaPage; Douglas Y Mah; Lindsey Malloy-Walton; Aya Miyazaki; Kara S Motonaga; Mary C Niu; Melissa Olen; Thomas Paul; Eric Rosenthal; Elizabeth V Saarel; Massimo Stefano Silvetti; Elizabeth A Stephenson; Reina B Tan; John Triedman; Nicholas H Von Bergen; Philip L Wackel Journal: Indian Pacing Electrophysiol J Date: 2021-07-29