Clinical Outcomes and Modes of Death in Timothy Syndrome. A Multicenter International Study of a Rare Disorder

Keith A. Dufendach, Katherine Timothy, Michael John Ackerman, Benjamin Blevins, Andreas Pflaumer, Susan Etheridge, James Perry, Nico A. Blom, Joel Temple, Devyani Chowdhury, Jonathan R. Skinner, Christopher Johnsrude, Andras Bratincsak, J. Martijn Bos, Maully Shah

Research output: Contribution to journalArticle

9 Citations (Scopus)

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.

Original languageEnglish (US)
JournalJACC: Clinical Electrophysiology
DOIs
StateAccepted/In press - Jan 1 2017

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Multicenter Studies
Hypoglycemia
Cardiac Arrhythmias
Syndactyly
Timothy syndrome
Inborn Genetic Diseases
Congenital Heart Defects
Implantable Defibrillators
Ventricular Fibrillation
Sudden Death
Heart Arrest
Terminology
Tertiary Care Centers
General Anesthesia
Registries
Retrospective Studies
Pediatrics
Mutation
Mortality

Keywords

  • Hypoglycemia
  • Sudden cardiac death
  • Syndactyly
  • T-wave alternans
  • Timothy syndrome
  • Ventricular fibrillation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Clinical Outcomes and Modes of Death in Timothy Syndrome. A Multicenter International Study of a Rare Disorder. / Dufendach, Keith A.; Timothy, Katherine; Ackerman, Michael John; Blevins, Benjamin; Pflaumer, Andreas; Etheridge, Susan; Perry, James; Blom, Nico A.; Temple, Joel; Chowdhury, Devyani; Skinner, Jonathan R.; Johnsrude, Christopher; Bratincsak, Andras; Bos, J. Martijn; Shah, Maully.

In: JACC: Clinical Electrophysiology, 01.01.2017.

Research output: Contribution to journalArticle

Dufendach, KA, Timothy, K, Ackerman, MJ, Blevins, B, Pflaumer, A, Etheridge, S, Perry, J, Blom, NA, Temple, J, Chowdhury, D, Skinner, JR, Johnsrude, C, Bratincsak, A, Bos, JM & Shah, M 2017, 'Clinical Outcomes and Modes of Death in Timothy Syndrome. A Multicenter International Study of a Rare Disorder', JACC: Clinical Electrophysiology. https://doi.org/10.1016/j.jacep.2017.08.007
Dufendach, Keith A. ; Timothy, Katherine ; Ackerman, Michael John ; Blevins, Benjamin ; Pflaumer, Andreas ; Etheridge, Susan ; Perry, James ; Blom, Nico A. ; Temple, Joel ; Chowdhury, Devyani ; Skinner, Jonathan R. ; Johnsrude, Christopher ; Bratincsak, Andras ; Bos, J. Martijn ; Shah, Maully. / Clinical Outcomes and Modes of Death in Timothy Syndrome. A Multicenter International Study of a Rare Disorder. In: JACC: Clinical Electrophysiology. 2017.
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AU - Timothy, Katherine

AU - Ackerman, Michael John

AU - Blevins, Benjamin

AU - Pflaumer, Andreas

AU - Etheridge, Susan

AU - Perry, James

AU - Blom, Nico A.

AU - Temple, Joel

AU - Chowdhury, Devyani

AU - Skinner, Jonathan R.

AU - Johnsrude, Christopher

AU - Bratincsak, Andras

AU - Bos, J. Martijn

AU - Shah, Maully

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N2 - 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.

AB - 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.

KW - Hypoglycemia

KW - Sudden cardiac death

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KW - T-wave alternans

KW - Timothy syndrome

KW - Ventricular fibrillation

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