Natural History and Risk Stratification in Andersen-Tawil Syndrome Type 1

Mazzanti, Andrea; Guz, Dmitri; Trancuccio, Alessandro; Pagan, Eleonora; Kukavica, Deni; Chargeishvili, T; Olivetti, Natália Quintella Sangiorgi; Biernacka, Katarzyna; Sacilotto, Luciana; Sarquella‐Brugada, Georgia; Campuzano, Òscar; Nof, Eyal; Anastasakis, A; Sansone, Valeria; Jiménez‐Jáimez, Juan; Cruz, Fernando E.S.; Sánchez-Quiñones, Jessica; Hernández-Afonso, Julio; Fuentes, María Eugenia; Średniawa, Beata; Garoufi, Anastasia; Andršová, Irena; Izquierdo, Maite; Marinov, Rumen; Danon, Asaf; Expósito-García, Víctor; García-Fernández, Amaya; Muñoz‐Esparza, Carmen; Ortiz, Martín; Zienciuk-Krajka, Agnieszka; Tavazzani, Elisa; Monteforte, Nicola; Bloise, Raffaella; Marino, Maira; Memmi, Mirella; Napolitano, Carlo; Zorio, Esther; Monserrat, Lorenzo; Bagnardi, Vincenzo; Priori, Silvia G.

doi:10.1016/j.jacc.2020.02.033

Cited by 52 publications

(61 citation statements)

References 29 publications

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“…An accurate 3D morphometric analysis of the face could help in improving early recognition of ATS, particularly when the distinctive facial features are not clearly manifest, in order to start an effective management and follow‐up of the disease. This is especially important because recent longitudinal data on cardiac involvement provide evidence that the clinical course of patients with ATS type 1 is characterized by a high rate of life‐threatening adverse events (Mazzanti et al, 2020).…”

Section: Discussionmentioning

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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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: Discussionmentioning

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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“…The benefits of the early identification of patients with ATS is determining an adequate treatment, management, stratification of the risk of SCD and avoiding the use of amiodarone to prevent fatal outcomes 35,36 , the monitoring of potassium levels avoids related hypokalemic alterations with weakness, and in some rare cases refer for plastic surgery intervention, to improve the quality of life of the patient. More studies are needed with a focus on the participation of genetics factors that lead to SCD and their interaction with environmental variables.…”

Section: Discussionmentioning

confidence: 99%

Andersen-Tawil Syndrome with High Risk of Sudden Cardiac Death in Four Mexican Patients. Cardiac and Extra-Cardiac Phenotypes

Barrón-Díaz

Totomoch-Serra

Escobar-Cedillo

et al. 2021

RIC

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Background: Andersen-Tawil syndrome (ATS) is a cardiac channelopathy that is inherited in an autosomal dominant way, and it is characterized by a triad of periodic paralysis, ventricular arrhythmias, and includes some dysmorphic features with incomplete penetrance and variable expression that result in a challenging diagnosis. Objective: The objective of the study was to describe the cardiac and extra-cardiac phenotype in a cohort of patients with ATS at risk of sudden cardiac death (SCD) to improve its early clinical identification. Methods: In an observational, transversal study, with a deviant case sampling, four female patients with ATS at high risk of SCD were included in the study. They carried the heterozygous pathogenic variants c.407C>T [p.Ser136Phe], c.652C>T [p.Arg218Trp] (n=2), and c.431G>C [p.Gly144Ala] in the KCNJ2 gene. Patients were evaluated by a cardiologist, a clinical geneticist, and a physiatrist. Results: One patient had the classical facial phenotype and the other three had subtle manifestations. The group of patients presented a diverse set of clinical data such as: triangular face, broad forehead, broadening of medial eyebrows, auricular pits, low-set ears, eyelid ptosis, thin lips, mandibular hypoplasia, and diverse types of dental alterations, single transverse palmar crease, camptodactyly, and syndactyly. Long-exercise test showed a decrement in the percentage amplitude up to 44%, classifying patients in IV or V types according to Fournier's scale. Conclusions: Extracardiac manifestations were a common finding in this series of ATS type1 at high risk of SCD. Its recognition could help the clinician in the early identification of patients with ATS, especially for the cardiologist since they are commonly referred only for evaluation of ventricular arrhythmias. (REV INVEST CLIN. [AHEAD OF PRINT])

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“…Symptomes in ATS1 are often mild and long-term prognosis is thought to be relatively more favourable compared to other channelopathies. A recent multicenter study on the largest ATS1 patient cohort (n = 118) assembled to date, however, showed that adverse cardiac events are more frequent in ATS1 than previously anticipated 14 . Most importantly, pharmacological therapy including the use of β-blockers alone or in combination with class Ic antiarrhythmic agents failed to reduce the occurrence of life-threathening arrhythmic events, despite suppressing arrhythmic symtpomes effectively 14 .…”

Section: Introductionmentioning

confidence: 86%

“…A recent multicenter study on the largest ATS1 patient cohort (n = 118) assembled to date, however, showed that adverse cardiac events are more frequent in ATS1 than previously anticipated 14 . Most importantly, pharmacological therapy including the use of β-blockers alone or in combination with class Ic antiarrhythmic agents failed to reduce the occurrence of life-threathening arrhythmic events, despite suppressing arrhythmic symtpomes effectively 14 . These findings highlight the demand for evidence-based treatment strategies in ATS1, including the development of specific activators of IK1.…”

Section: Introductionmentioning

confidence: 86%

Impaired cytoplasmic domain interactions cause co-assembly defect and loss of function in the p.Glu293Lys KNCJ2 variant isolated from an Andersen–Tawil syndrome patient

Déri

Borbás

Hartai

et al. 2020

Cardiovascular Research

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Aims Subunit interactions at the cytoplasmic domain interface (CD-I) have recently been shown to control gating in inward rectifier potassium channels. Here we report the novel KCNJ2 variant p.Glu293Lys that has been found in a patient with Andersen-Tawil Syndrome type 1 (ATS1), causing amino acid substitution at the CD-I of the inward rectifier potassium channel subunit Kir2.1. Neither has the role of Glu293 in gating control been investigated, nor has a pathogenic variant been described at this position. This study aimed to assess the involvement of Glu293 in CD-I subunit interactions and to establish the pathogenic role of the p.Glu293Lys variant in ATS1. Methods and Results The p.Glu293Lys variant produced no current in homomeric form and showed dominant negative effect over wild type (WT) subunits. Immunocytochemical labelling showed the p.Glu293Lys subunits to distribute in the subsarcolemmal space. Salt bridge prediction indicated the presence of an intersubunit salt bridge network at the CD-I of Kir2.1, with the involvement of Glu293. Subunit interactions were studied by the NanoBiT split reporter assay. Reporter constructs carrying NanoBiT tags on the intracellular termini produced no bioluminescent signal above background with the p.Glu293Lys variant in homomeric configuration and significantly reduced signals in cells co-expressing WT and p.Glu293Lys subunits simultaneously. Extracellularly presented reporter tags, however, generated comparable bioluminescent signals with heteromeric WT and p.Glu293Lys subunits and with homomeric WT channels. Conclusions Loss of function and dominant negative effect confirm the causative role of p.Glu293Lys in ATS1. Co-assembly of Kir2.1 subunits is impaired in homomeric channels consisting of p.Glu293Lys subunits and is partially rescued in heteromeric complexes of WT and p.Glu293Lys Kir2.1 variants. These data point to an important role of Glu293 in mediating subunit assembly, as well as in gating of Kir2.1 channels. Translational perspective Andersen-Tawil Syndrome (ATS) is a rare genetic disorder characterized by the triad of periodic paralysis, dysmorphic features and ventricular arrhythmias. Symptoms can be mild and atypical, therefore, genetic screening of affected families is pivotal. This study describes the p.Glu293Lys variant of KCNJ2 encoding the Kir2.1 ion channel subunit as pathogenic, thereby aiding genetic testing of ATS. The study also identifies disturbed interactions between the cytoplasmic domains of Kir2.1 subunits as the molecular mechanism of loss-of-function in the p.Glu293Lys variant. Targeting cytoplasmic domain interactions may represent a promising strategy for the development of Kir2.1 agonists.

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Natural History and Risk Stratification in Andersen-Tawil Syndrome Type 1

Cited by 52 publications

References 29 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

Andersen-Tawil Syndrome with High Risk of Sudden Cardiac Death in Four Mexican Patients. Cardiac and Extra-Cardiac Phenotypes

Impaired cytoplasmic domain interactions cause co-assembly defect and loss of function in the p.Glu293Lys KNCJ2 variant isolated from an Andersen–Tawil syndrome patient

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