Clinical Outcomes and Modes of Death in Timothy Syndrome

Dufendach, Keith; Timothy, Katherine W.; Ackerman, Michael J.; Blevins, Benjamin; Pflaumer, Andreas; Etheridge, Susan P.; Perry, James C.; Blom, Nico A.; Temple, Joel; Chowdhury, Devyani; Skinner, Jonathan R.; Johnsrude, Christopher L.; Bratincsák, András; Bos, J. Martijn; Shah, Maully J.

doi:10.1016/j.jacep.2017.08.007

Cited by 42 publications

(35 citation statements)

References 26 publications

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“…These gain-of-function mutations result in increased calcium transport into cardiomyocytes, thereby prolonging QT interval and increasing risk of arrhythmia. The mainstay of therapy is beta-blockade [36].…”

Section: Standard Of Care Therapymentioning

confidence: 99%

Long QT Syndrome: Genetics and Future Perspective

et al. 2019

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Long QT syndrome (LQTS) is an inherited primary arrhythmia syndrome that may present with malignant arrhythmia and, rarely, risk of sudden death. The clinical symptoms include palpitations, syncope, and anoxic seizures secondary to ventricular arrhythmia, classically torsade de pointes. This predisposition to malignant arrhythmia is from a cardiac ion channelopathy that results in delayed repolarization of the cardiomyocyte action potential. The QT interval on the surface electrocardiogram is a summation of the individual cellular ventricular action potential durations, and hence is a surrogate marker of the abnormal cellular membrane repolarization. Severely affected phenotypes administered current standard of care therapies may not be fully protected from the occurrence of cardiac arrhythmias. There are 17 different subtypes of LQTS associated with monogenic mutations of 15 autosomal dominant genes. It is now possible to model the various LQTS phenotypes through the generation of patient-specific induced pluripotent stem cell-derived cardiomyocytes. RNA interference can silence or suppress the expression of mutant genes. Thus, RNA interference can be a potential therapeutic intervention that may be employed in LQTS to knock out mutant mRNAs which code for the defective proteins. CRISPR/Cas9 is a genome editing technology that offers great potential in elucidating gene function and a potential therapeutic strategy for monogenic disease. Further studies are required to determine whether CRISPR/Cas9 can be employed as an efficacious and safe rescue of the LQTS phenotype. Current progress has raised opportunities to generate in vitro human cardiomyocyte models for drug screening and to explore gene therapy through genome editing.

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Section: Standard Of Care Therapymentioning

confidence: 99%

Long QT Syndrome: Genetics and Future Perspective

et al. 2019

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“…First, because we only identify the classic TS missense mutation p.Gly406Arg, other mutations might have been missed since only 59% of patients with TS have the classic CACNA1C mutation. [ 5 ] Further study may be needed to examine whether there are other mutations (eg, p.Ser405Arg, p.Gly402Arg, and p.Cys1021Arg) in children with syndactyly with a TS-like phenotype. Second, due to the malignant course of TS with a reported average age at death of 2.5 years, [ 20 ] TS patients may not survive to undergo syndactyly-release surgery.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, such condition might not be suitable for children with LQTS as increased QTc interval is associated with an increased risk of torsades de pointes in this population. [ 28 ] Dufendach et al [ 5 ] report that 23% of patients die due to ventricular fibrillation and 76% of patients are treated with an implantable cardioverter-defibrillator during a 4.9 years follow-up in patients with TS. implantable cardioverter-defibrillators remain an option for patients with TS, especially for those with refractory arrhythmias.…”

Section: Discussionmentioning

confidence: 99%

“…implantable cardioverter-defibrillators remain an option for patients with TS, especially for those with refractory arrhythmias. [ 5 , 8 ] In the present study, all patients with QT prolongation are followed by phone and are alive in October 2019, including the patients with confirmed TS, who is 10 years of age.…”

Section: Discussionmentioning

confidence: 99%

“…Ventricular tachyarrhythmia is usually the leading cause of death at the age of 2.5 years on average. [ 4 ] The alternatively spliced exon 8A of the CACNA1C gene [ 5 ] results in the inactivation of the Ca v 1.2 L-type calcium channel and in a prolonged heart rate-corrected QT (QTc) of 480 to 700 ms, thus making the heart more susceptible to ventricular arrhythmias and even SCD. One case report of a Chinese child with TS has so far been reported.…”

Section: Introductionmentioning

confidence: 99%

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Clinical characterization and outcome of prolonged heart rate-corrected QT interval among children with syndactyly

Hao

Chen

et al. 2020

Medicine

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Prolonged heart rate-corrected QT (QTc) interval is an independent risk factor for sudden cardiac death, which is the hallmark of Timothy syndrome (TS). There are little data on children with syndactyly and QTc prolongation. To evaluate the characteristics and long-term outcomes in children with syndactyly, and to attempt to identify TS in patients with syndactyly and QTc prolongation. This is a retrospective case-control study of children with syndactyly who visited Beijing Jishuitan Hospital between July 2003 and February 2013. The patients with prolonged QTc intervals are matched 1:4 with patients without prolongation. Genetic testing of the CACNA1C gene is routinely performed in patients with QTc prolongation. The mean age at admission is 3.4 ± 2.3 years. Compared with the normal QTc group, those with QTc prolongation showed higher frequencies of congenital heart disease (11.8% vs 1.5%, P = .042), mental retardation and facial dysmorphia (11.8% vs 0, P = .004), and T wave alternans (23.5% vs 4.4%, P = .01). In the multivariable analysis, only T wave alternans (OR = 10.61, 95%CI: 1.39–81.16, P = .023) is independently associated with QTc prolongation in patients with syndactyly. One child with QTc prolongation had a mutation in the CACNA1C gene. No patients with prolonged QTs interval met the threshold for TS. Children with syndactyly and prolonged QTc interval had more multisystem diseases and electrocardiography abnormalities. T wave alternans is independently associated with QTc prolongation in patients with syndactyly.

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