Rarity and phenotypic heterogeneity provide challenges in the diagnosis of Andersen–Tawil syndrome: Two cases presenting with ECGs mimicking catecholaminergic polymorphic ventricular tachycardia (CPVT)

Tully, Ian; Atherton, J.; Hunt, Lauren; Ingles, Jodie; Semsarian, C.; McGaughran, Julie

doi:10.1016/j.ijcard.2015.07.069

Cited by 13 publications

(15 citation statements)

References 11 publications

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“…In these conditions, calcium transient dynamics was altered, as revealed by both prolonged recovery times of the calcium transients and multiple abnormal spontaneous calcium release events. Therefore, data presented here lead us to propose a potential molecular mechanism to explain the spontaneous arrhythmias as well as muscle weakness and periodic paralysis reported for ATS1 patients 5,6 . We hypothesize that, in addition to disrupting the Kir2.1-NaV1.5 channelosome at the sarcolemma 8,10 , ATS1 also leads to dysfunction of SR Kir2.1 channels, directly altering SR countercurrents, thus disrupting e-c coupling and intracellular Ca 2+ dynamics.…”

Section: Discussionmentioning

confidence: 67%

“…As an additional value, this model has permitted us to unravel a potential molecular mechanism for the phenotypic overlap between ATS1 and CPVT in some patients 5,6 , as well as a new actor in such an essential physiological function as e-c coupling in striated muscles. Based on the evidence presented here, we postulate that in addition to reduced IK1 and INa 8, 10 , some ATS1 mutations also lead to dysfunction of SR Kir2.1 channels, directly altering SR countercurrents, disrupting e-c coupling and intracellular Ca 2+ dynamics that result in stress-increased calcium-mediated arrhythmias that mimic CPVT.…”

Section: Discussionmentioning

confidence: 99%

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Dual Dysfunction of Kir2.1 Underlies Conduction and Excitation-Contraction Coupling Defects Promoting Arrhythmias in a Mouse Model of Andersen-Tawil Syndrome Type 1

Macías

González-Guerra

Moreno-Manuel

et al. 2021

Preprint

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Andersen-Tawil Syndrome (ATS) is associated with life threatening arrhythmias of unknown mechanism. We report on a mouse model carrying the trafficking-deficient mutant Kir2.1Δ314-315. The mouse recapitulates the electrophysiological phenotype of type 1 (ATS1), with slower conduction velocities in response to flecainide, QT prolongation exacerbated by isoproterenol, and increased vulnerability to calcium-mediated arrhythmias resembling catecholaminergic polymorphic ventricular tachycardia (CPVT). Kir2.1Δ314-315 expression significantly reduced inward rectifier K+ and Na+ inward currents, depolarized resting membrane potential and prolonged action potential duration. Immunolocalization in wildtype cardiomyocytes and skeletal muscle cells revealed a novel sarcoplasmic reticulum (SR) microdomain of functional Kir2.1 channels contributing to intracellular Ca2+ homeostasis. Kir2.1Δ314-315 cardiomyocytes showed defects in SR Kir2.1 localization and function, which contributed to abnormal spontaneous Ca2+ release events. This is the first in-vivo demonstration of a dual arrhythmogenic mechanism of ATS1 defects in Kir2.1 channel function at the sarcolemma and the SR, with overlap between ATS1 and CPVT.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Dual Dysfunction of Kir2.1 Underlies Conduction and Excitation-Contraction Coupling Defects Promoting Arrhythmias in a Mouse Model of Andersen-Tawil Syndrome Type 1

Macías

González-Guerra

Moreno-Manuel

et al. 2021

Preprint

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“…However, during syncope no cardiac arrhythmias were documented. Recently, Tully et al [ 20 ] described the detection of the novel variant in a family with diagnosed ATS and concluded that the disease is likely caused by the variation. Our results verify the authors’ assumption that this variant results in clinical ATS phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a novel KCNJ2 sequence variant detected in Andersen-Tawil syndrome patients

et al. 2017

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BackgroundMutations in the KCNJ2 gene encoding the ion channel Kir2.1 have been linked to the Andersen-Tawil syndrome (ATS). Molecular genetic screening performed in a family exhibiting clinical ATS phenotypes unmasked a novel sequence variant (c.434A > G, p.Y145C) in this gene. The aim of this study was to investigate the effect of this variant on Kir2.1 ion channel functionality.MethodsMutant as well as wild type GFP tagged Kir2.1 channels were expressed in HEK293 cells. In order to examine the effect of the new variant, electrophysiological measurements were performed using patch clamp technique. Cellular localization of the mutant in comparison to the wild type ion channel was analyzed by confocal laser scanning microscopy.ResultsThe currents of cells expressing only mutant channels or a mixture of wild type and mutant were significantly reduced compared to those expressing wild type (WT) channels (p < 0.01). Whereas WT expressing cells exhibited at −120 mV an averaged current of −4.5 ± 1.9 nA, the mutant generates only a current of −0.17 ± 0.07 nA. A co-expression of mutant and WT channel generates only a partial rescue of the WT current. Confocal laser scanning microscopy indicated that the novel variant is not interfering with synthesis and/or protein trafficking.ConclusionsThe detected sequence variant causes loss-of-function of the Kir2.1 channel and explains the clinical phenotypes observed in Andersen-Tawil syndrome patients.

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“…Due to the recent discovery of TRDN 47 , CALM1 44 , and TECRL 55 genes as causes of CPVT, their inclusion in previous guidelines had not been contemplated, but we recommend screening after exclusion of RYR2 and CASQ as causes of this disease. Other genes to consider in a genetic test are KCNJ2 [71][72][73][74] and ANKB 75 .…”

Section: Genetic Testingmentioning

confidence: 99%

Basic and Clinical Insights in Catecholaminergic (Familial) Polymorphic Ventricular Tachycardia

Márquez¹,

Totomoch-Serra²,

Rueda³

et al. 2019

RIC

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Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal disease, whose characteristic ventricular tachycardias are adrenergic-dependent. Although rare, CPVT should be considered in the differential diagnosis of young individuals with exercise-induced syncope. Mutations in five different genes (RYR2, CASQ2, CALM1, TRDN, and TECRL) are associated with the CPVT phenotype, although RYR2 missense mutations are implicated in up to 60 % of all CPVT cases. Genetic testing has an essential role in the diagnosis, management, pre-symptomatic diagnosis, counseling, and treatment of the proband; furthermore, genetic information can be useful for offspring and relatives. By expert consensus, CPVT gene testing is a Class I recommendation for patients with suspected CPVT. Beta-adrenergic and calcium-channel blockers are the cornerstones of treatment due to the catecholaminergic dependence of the arrhythmias. Unresponsive patients are treated with an implantable cardioverter-defibrillator to reduce the risk of sudden cardiac death. In the present article, a brief review of the genetic and molecular mechanisms of this intriguing disease is provided.

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Rarity and phenotypic heterogeneity provide challenges in the diagnosis of Andersen–Tawil syndrome: Two cases presenting with ECGs mimicking catecholaminergic polymorphic ventricular tachycardia (CPVT)

Cited by 13 publications

References 11 publications

Dual Dysfunction of Kir2.1 Underlies Conduction and Excitation-Contraction Coupling Defects Promoting Arrhythmias in a Mouse Model of Andersen-Tawil Syndrome Type 1

Dual Dysfunction of Kir2.1 Underlies Conduction and Excitation-Contraction Coupling Defects Promoting Arrhythmias in a Mouse Model of Andersen-Tawil Syndrome Type 1

Characterization of a novel KCNJ2 sequence variant detected in Andersen-Tawil syndrome patients

Basic and Clinical Insights in Catecholaminergic (Familial) Polymorphic Ventricular Tachycardia

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