Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal-Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest

Altmann, Helene M.; Tester, David J.; Will, Melissa L.; Middha, Sumit; Evans, Jared M.; Eckloff, Bruce W.; Ackerman, Michael J.

doi:10.1161/circulationaha.115.015397

Cited by 91 publications

(90 citation statements)

References 27 publications

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“…The case records of 276 patients in the Boston Children's Hospital LQTS database were reviewed, of whom 104 were not included on the basis of age <4 years (25), no participation in competitive or recreational activities (19), declined study participation, no response to questionnaire or inadequate information (53), patients with disease‐associated gene variants but no identifiable phenotype (4), and other conditions: Timothy syndrome (1), Andersen‐Tawil (1) and triadin knockout syndrome (1) 16. In the 19 patients who responded but actively avoided activities, the median QTc was 460 ms (IQR 442, 469), of whom 2 were symptomatic prior to diagnosis, both with QTc intervals >500 ms (504 and 521 ms).…”

Section: Resultsmentioning

confidence: 99%

Cardiac Events During Competitive, Recreational, and Daily Activities in Children and Adolescents With Long QT Syndrome

Chambers

Ladouceur

Alexander

et al. 2017

JAHA

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BackgroundThe 2005 Bethesda Conference Guidelines advise patients with long QT syndrome against competitive sports. We assessed cardiac event rates during competitive and recreational sports, and daily activities among treated long QT syndrome patients.Methods and ResultsLong QT syndrome patients aged ≥4 years treated with anti‐adrenergic therapy were included. Demographics included mechanism of presentation, corrected QT interval pretreatment, symptom history, medication compliance, and administration of QT‐prolonging medications. Corrected QT interval ≥550 ms or prior cardiac arrest defined high risk. Sports were categorized by cardiovascular demand per the 2005 Bethesda Conference Guidelines. Each was classified as recreational or competitive. One hundred seventy‐two patients (90; 52% female) with median age 15.2 years (interquartile range 11.4, 19.4) were included. Evaluation was performed for family history (102; 59%), incidental finding (34; 20%), and symptoms (36; 21%). Median corrected QT interval was 474 ms (interquartile range 446, 496) and 14 patients (8%) were deemed high risk. Treatment included β‐blockers (171; 99%), implantable cardioverter‐defibrillator (27; 16%), left cardiac sympathetic denervation (7; 4%), and pacemaker (3; 2%). Sports participation was recreational (66; 38%) or competitive (106; 62%), with 92 (53%) exercising against the Bethesda Conference Guidelines. There were no cardiac events in competitive athletes and no deaths. There were 13 cardiac events in 9 previously symptomatic patients during either recreational exercise or activities of daily life.ConclusionsIn this cohort of appropriately managed children with long QT syndrome, cardiac event rates were low and occurred during recreational but not competitive activities. This study further supports the need for increased assessment of arrhythmia risk during exercise in this patient population.

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Section: Resultsmentioning

confidence: 99%

Cardiac Events During Competitive, Recreational, and Daily Activities in Children and Adolescents With Long QT Syndrome

Chambers

Ladouceur

Alexander

et al. 2017

JAHA

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“…1a, b). Exons 1-8 of TRDN encode the first 264 residues of both cardiac and skeletal triadin isoforms, raising the possibility that mutations in these exons may affect both cardiac and skeletal muscle function [7].…”

Section: The Role Of Triadin-1 In Ventricular Myocytesmentioning

confidence: 99%

“…A subsequent study in 2015 performed whole exome sequencing on 33 patients with a long QT syndrome phenotype but no identified underlying mutation in normal candidate genes [7]. Five index patients, all of 10 years or younger in age, were identified from different families; they had QTc intervals ranging from 464 to 500 ms and had all experienced exertion/stress induced syncope and cardiac arrest by 3 years of age [7].…”

Section: Trdn Mutations Associated With Human Ventricular Arrhythmiamentioning

confidence: 99%

“…Five index patients, all of 10 years or younger in age, were identified from different families; they had QTc intervals ranging from 464 to 500 ms and had all experienced exertion/stress induced syncope and cardiac arrest by 3 years of age [7]. All patients exhibited extensive T wave inversion in precordial leads V 1 to V 4 .…”

Section: Trdn Mutations Associated With Human Ventricular Arrhythmiamentioning

confidence: 99%

“…Whilst higher molecular weight isoforms can be detected in the heart, the predominant cardiac isoform is the Trisk 32 (32 kDa) isoform [4]. Accumulating evidence from recent mouse and human studies has implicated loss of functional triadin with heritable ventricular arrhythmia and risk of sudden death [2,[5][6][7][8]. Here we summarize briefly the evidence for involvement of TRDN mutations in human ventricular arrhythmia, discuss potential underlying mechanisms of arrhythmogenesis and summarize present and potential future treatment avenues.…”

Section: Introductionmentioning

confidence: 96%

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Triadin mutations - a cause of ventricular arrhythmias in children and young adults

Hancox

James

Walsh

et al. 2017

J Congenit Heart Dis

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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 Ca 2+ handling and susceptibility to adrenergic agonist provoked arrhythmias. In particular, cellular electrophysiology experiments have provided evidence of reduced Ca 2+ induced inactivation of L-type Ca 2+ channels consequent to TRDN knockout. A number of reports since 2012 have identified patients with a CPVT phenotype, some of whom also exhibit prolonged QT c 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 Ca 2+ 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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Genetics of Long QT and Short QT Syndromes

Maragna

Mazzanti

Priori

2017

Encyclopedia of Life Sciences

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Long QT syndrome (LQTS) is the best described inheritable arrhythmogenic disorder. It is characterised by a increased duration of cardiac action potential secondary either to mutations that produce a loss‐of‐function of potassium channels responsible for cardiac repolarisation or to gain‐of‐function alterations of sodium channels responsible for cardiac depolarisation. Seventeen genes have been associated with LQTS. The first three genotypes discovered (LQT1–LQT3) account for 95% of genotype‐positive cases. Genetic analysis allows to identify the pathogenic genetic defect in 80% of patients and plays a crucial role in the diagnosis, risk stratification and treatment. Conversely, short QT syndrome (SQTS) is the latest described inheritable arrhythmogenic disease, and its genetic basis has been poorly clarified. It is characterised by an abnormal shortening of the cardiac repolarisation, which may result either from gain‐of‐function mutations of potassium channels responsible for cardiac repolarisation or from a diminished function of voltage‐dependent‐L‐type calcium channels responsible for cardiac depolarisation. The five genetic forms of the disease identified account for only 20% of SQTS patients. Therefore, genetic analysis portends a limited contribution to the diagnosis and management of SQTS patients. Key Concepts Long QT syndrome (LQTS) is the best described monogenic inherited arrhythmogenic disorder, with 17 disease‐related genes described to date. The first three genotypes discovered represent about 75% of all LQTS cases. The common pathophysiological substrate of LQTS variants is represented by a prolongation of cardiac repolarisation that can be secondary either to loss‐of‐function defects of potassium channels responsible for cardiac repolarisation or to gain‐of‐function alterations of sodium channels responsible for cardiac depolarisation. Genetic analysis allows to identify the pathogenic defect in 80% of LQTS patients and therefore plays a crucial role in the diagnosis, risk stratification and therapeutic approach of LQTS patients. Short QT syndrome (SQTS) is the latest described inherited arrhythmogenic disorder, and its genetic basis has been scarcely understood. To date, five genetic forms of the disease have been identified. Genetic analysis allows to identify the pathogenic defect in only 20% of SQTS affected individuals. The pathophysiological substrate of SQTS resides in an abnormal shortening of cardiac repolarisation, which can be secondary to gain‐of‐function mutations harboured in potassium channels or to loss‐of‐function defects of voltage‐dependent L‐type calcium channels. Due to the lack of genotype–phenotype correlation information to this date and due to the low yield of genetic testing, in SQTS genetic analysis does not help in risk stratification and clinical management of affected individuals.

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Homozygous/Compound Heterozygous Triadin Mutations Associated With Autosomal-Recessive Long-QT Syndrome and Pediatric Sudden Cardiac Arrest

Cited by 91 publications

References 27 publications

Cardiac Events During Competitive, Recreational, and Daily Activities in Children and Adolescents With Long QT Syndrome

Cardiac Events During Competitive, Recreational, and Daily Activities in Children and Adolescents With Long QT Syndrome

Triadin mutations - a cause of ventricular arrhythmias in children and young adults

Genetics of Long QT and Short QT Syndromes

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