Therapeutic management of ventricular arrhythmias in Andersen-Tawil syndrome

Maffè, Stefano; Paffoni, Paola; Bergamasco, Luca; Dellavesa, Pierfranco; Zenone, Franco; Baduena, Lara; Pardo, Nicolò Franchetti; Careri, Giulia; Facchini, Emanuela; Sansone, Valeria; Parravicini, Umberto

doi:10.1016/j.jelectrocard.2019.10.009

Cited by 10 publications

(12 citation statements)

References 12 publications

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“…Andersen–Tawil syndrome (ATS, OMIM #170390) is a hereditable autosomic dominant channelopathy with prevalence estimated at about 1:500,000 (Maffè et al, 2020). The disorder is associated with mutations in the KCNJ2 gene on chromosome 17 (ATS type 1), which encodes for Kir2.1, an inward rectifier potassium channel involved in stabilizing resting membrane potential and modulating the repolarization phase in excitable cells (Plaster et al, 2001); recently, also KCNJ5 gene encoding for Kir3.4 potassium channel has been associated with the disorder (ATS type 2) (Kokunai et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…However, patients may distinctly exhibit only one or none of them: the great phenotypic variability, even intrafamilial, and the rarity of the disease may lead to a challenging diagnosis (Ardissone, Sansone, Colleoni, Bernasconi, & Moroni, 2017). On the other hand, because some of the cardiac manifestations of ATS can be dangerous and predispose to cardiac arrest (Peters, Schulze‐Bahr, Etheridge, & Tristani‐Firouzi, 2007; Airey, Etheridge, Tawil, & Tristani‐Firouzi, 2009; Maffè et al, 2020), establishing an early and accurate diagnosis of the disorder is essential to start appropriate treatment and follow‐up. The recognition of distinctive facial features can help early diagnosis of ATS, but manifestations may be subtle and therefore unnoticeable on routine physical examination (Canun, Perez, & Beirana, 1999; Tristani‐Firouzi, & Etheridge, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Distinctive facial features in Andersen–Tawil syndrome: A three‐dimensional stereophotogrammetric analysis

Dolci

Sansone

Gibelli

et al. 2020

American J of Med Genetics Pt A

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Andersen–Tawil syndrome (ATS) is a rare potassium channelopathy causing periodic paralysis, cardiac arrhythmias, and dysmorphic features. A detailed analysis of the face could facilitate diagnosis of ATS, as approximately 30% of patients do not show variants in KCNJ2 gene, and diagnosis is established by clinical findings. We aimed to characterize the face in ATS through a quantitative approach, as facial anomalies may be unnoticed on visual inspection. Facial images of 12 subjects with genetically confirmed ATS (six males, six females, age 5–67 years) were acquired through stereophotogrammetry. Using 38 soft‐tissue landmarks, linear distances, angles, and ratios were calculated and expressed as z‐score values, with reference to 477 healthy subjects matched for sex and age. All patients showed decreased lower facial height with shortening of philtrum (mean z‐score ± SD: −1.5 ± 0.9), smaller mid and lower facial depths (−1.9 ± 0.7; −2.3 ± 0.9), short palpebral fissures (right −1.2 ± 0.4; left −1.6 ± 0.6), smaller mandibular ramus length (−2.1 ± 0.4), and increased nasal width/length ratio (1.4 ± 0.5) with smaller nostril axis length (right −1.8 ± 0.8, left −1.6 ± 0.7). Hypertelorism and low‐set ears were detected in two‐thirds of patients. The study quantified facial dysmorphysm in ATS, extending information about known features, and detecting unrecorded philtrum and nostril characteristics, which may be distinctive traits of the disorder.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Distinctive facial features in Andersen–Tawil syndrome: A three‐dimensional stereophotogrammetric analysis

Dolci

Sansone

Gibelli

et al. 2020

American J of Med Genetics Pt A

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“…It is based on the use of class Ic antiarrhythmic drugs (e.g., flecainide and propafenone) and amiodarone to reduce arrhythmia susceptibility. 1 Nowadays, even though it is not nearly 100% effective, flecainide is the most widely used therapy in ATS patients, 46 , 115–117 but without consideration of specific mechanisms. Both flecainide and propafenone bind to the cytoplasmic portion of Kir2.1, 43 , 44 they also reduce Na V 1.5 channel function.…”

Section: From Mechanism To Therapymentioning

confidence: 99%

Molecular stratification of arrhythmogenic mechanisms in the Andersen Tawil syndrome

Manuel

Gutiérrez

Pedrosa

et al. 2022

Cardiovascular Research

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Andersen Tawil Syndrome (ATS) is a rare inheritable disease associated with loss-of-function mutations in KCNJ2, the gene coding the strong inward rectifier potassium channel Kir2.1, which forms an essential membrane protein controlling cardiac excitability. ATS is usually marked by a triad of periodic paralysis, life-threatening cardiac arrhythmias and dysmorphic features, but its expression is variable and not all patients with a phenotype linked to ATS have a known genetic alteration. The mechanisms underlying this arrhythmogenic syndrome are poorly understood. Knowing such mechanisms would be essential to distinguish ATS from other channelopathies with overlapping phenotypes and to develop individualized therapies. For example, the recently suggested role of Kir2.1 as a countercurrent to sarcoplasmic calcium reuptake might explain the arrhythmogenic mechanisms of ATS and its overlap with catecholaminergic polymorphic ventricular tachycardia (CPVT). Here we summarize current knowledge on the mechanisms of arrhythmias leading to sudden cardiac death in ATS. We first provide an overview of the syndrome and its pathophysiology, from the patient´s bedside to the protein, and discuss the role of essential regulators and interactors that could play a role in cases of ATS. The review highlights novel ideas related to some post-translational channel interactions with partner proteins that might help define the molecular bases of the arrhythmia phenotype. We then propose a new all-embracing classification of the currently known ATS loss-of-function mutations according to their position in the Kir2.1 channel structure and their functional implications. We also discuss specific ATS pathogenic variants, their clinical manifestations and treatment stratification. The goal is to provide a deeper mechanistic understanding of the syndrome toward the development of novel targets and personalized treatment strategies.

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“…83 β-blockers are the most frequently used prophylactic drugs, alone or in combination with amiodarone or flecainide. 44 Counseling on the risks of QT prolonging drugs, excessive adrenergic stimulation, and hypokalemia is important. 35 β-blockers are indicated in asymptomatic individuals meeting diagnostic criteria, including those who have a pathogenic variant on molecular testing and a normal QTc interval.…”

Section: Managementmentioning

confidence: 99%

“…Twelve-lead ECG with BVT with RBBB pattern at rest. 44 BVT indicates bidirectional ventricular tachycardia; ECG, electrocardiogram; FC, heart rate (HR); RBBB, right bundle branch block.…”

Section: Clinical Diagnosismentioning

confidence: 99%

Andersen–Tawil Syndrome

Pérez‐Riera

Barbosa‐Barros

Samesina

et al. 2020

Cardiology in Review

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Andersen-Tawil syndrome (ATS) is a very rare orphan genetic multisystem channelopathy without structural heart disease (with rare exceptions). ATS type 1 is inherited in an autosomal dominant fashion and is caused by mutations in the KCNJ2 gene, which encodes the α subunit of the K + channel protein Kir2.1 (in ≈ 50-60% of cases). ATS type 2 is in turn linked to a rare mutation in the KCNJ5-GIRK4 gene that encodes the G protein-sensitive-activated inwardly rectifying K + channel Kir3.4 (15%), which carries the acetylcholine-induced potassium current. About 30% of cases are de novo/ sporadic, suggesting that additional as-yet unidentified genes also cause the disorder. A triad of periodic muscle paralysis, repolarization changes in the electrocardiogram, and structural body changes characterize ATS. The typical muscular change is episodic flaccid muscle weakness. Prolongation of the QU/QUc intervals and normal or minimally prolonged QT/QTc intervals with a tendency to ventricular arrhythmias are typical repolarization changes. Bidirectional ventricular tachycardia is the hallmark ventricular arrhythmia, but also premature ventricular contractions, and rarely, polymorphic ventricular tachycardia of torsade de pointes type may be present. Patients with ATS have characteristic physical developmental dysmorphisms that affect the face, skull, limbs, thorax, and stature. Mild learning difficulties and a distinct neurocognitive phenotype (deficits in executive function and abstract reasoning) have been described. About 60% of affected individuals have all features of the major triad. The purpose of this review is to present historical aspects, nomenclature (observations/criticisms), epidemiology, genetics, electrocardiography, arrhythmias, electrophysiological mechanisms, diagnostic criteria/ clues of periodic paralysis, prognosis, and management of ATS.

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Therapeutic management of ventricular arrhythmias in Andersen-Tawil syndrome

Cited by 10 publications

References 12 publications

Distinctive facial features in Andersen–Tawil syndrome: A three‐dimensional stereophotogrammetric analysis

Distinctive facial features in Andersen–Tawil syndrome: A three‐dimensional stereophotogrammetric analysis

Molecular stratification of arrhythmogenic mechanisms in the Andersen Tawil syndrome

Andersen–Tawil Syndrome

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