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Martin Tristanifirouzi - One of the best experts on this subject based on the ideXlab platform.

  • kir 2 1 channelopathies the andersen tawil Syndrome
    Pflügers Archiv: European Journal of Physiology, 2010
    Co-Authors: Martin Tristanifirouzi, Susan P Etheridge
    Abstract:

    As a multisystem disorder, Andersen–Tawil Syndrome (ATS) is rather unique in the family of channelopathies. The full spectrum of the disease is characterized by ventricular arrhythmias, dysmorphic features, and periodic paralysis. Most ATS patients have a mutation in the ion channel gene, KCNJ2, which encodes the inward rectifier K+ channel Kir2.1, a component of the inward rectifier I K1. I K1 provides repolarizing current during the most terminal phase of repolarization and is the primary conductance controlling the diastolic membrane potential. Thus, ATS is a disorder of cardiac repolarization. The chapter will discuss the most recent data concerning the genetic, cellular, and clinical data underlying this unique disorder.

  • resuscitated sudden cardiac death in andersen tawil Syndrome
    Heart Rhythm, 2009
    Co-Authors: Kelly J Airey, Rabi Tawil, Susan P Etheridge, Martin Tristanifirouzi
    Abstract:

    Andersen-Tawil Syndrome (ATS) is an autosomal dominant or sporadic disorder characterized by ventricular arrhythmias, periodic paralysis and distinctive facial and skeletal dysmorphology [1-3]. ATS is notable for its variable penetrance (not all subjects manifest all three phenotypes) and variable expressivity (the severity of the expressed phenotype varies considerably). The neuromuscular manifestations of ATS consist of intermittent weakness, often in the setting of progressive interictal weakness. The distinctive physical characteristics include low-set ears, micrognathia, syndactyly, clinodactyly, short stature and scoliosis. Cardiac manifestations of ATS include QT and QU interval prolongation, prominent U waves, frequent premature ventricular contractions (PVCs), polymorphic ventricular tachycardia (VT) and bidirectional VT [3,4]. Although the burden of ventricular ectopy is often high in patients with ATS [5], degeneration into life-threatening arrhythmias is relatively uncommon [6]. Distinguishing individuals with stable, but frequent ventricular ectopy and those at risk for sudden cardiac death remains a challenge. Dominant-negative mutations in KCNJ2, the gene encoding the inward rectifier potassium channel Kir2.1, account for the majority of ATS cases. However, nearly 30% of ATS patients do not have an identifiable mutation in KCNJ2, confirming the genetic heterogeneity of this disorder [7]. Interestingly, there are no obvious phenotypic differences that distinguish individuals with and those without a mutation in KCNJ2. Likewise, it is not clear that patients with KCNJ2 mutations are at greater, lower or similar risk of life-threatening arrhythmias, compared to those who are KCNJ2-mutation negative. In this report, we present a 15-year-old female with KCNJ2-mutation negative ATS who experienced a life-threatening cardiac event with devastating clinical consequences.

  • flecainide suppresses bidirectional ventricular tachycardia and reverses tachycardia induced cardiomyopathy in andersen tawil Syndrome
    Journal of Cardiovascular Electrophysiology, 2007
    Co-Authors: A Oscar M D Pellizzon, Martin Tristanifirouzi, M Luis D Kalaizich, J Louis M D Ptacek, D Mario M D Gonzalez
    Abstract:

    Bidirectional ventricular tachycardia (BVT), although a rare arrhythmia in the general population, is frequently observed in patients with Andersen-Tawil Syndrome and long QT interval. However, the pharmacologic treatment of this arrhythmia remains unknown. In the present study, we documented the favorable antiarrhythmic action of flecainide in a young woman with sustained BVT and Andersen-Tawil Syndrome. She presented with incessant BVT that could only be terminated with flecainide. During sinus rhythm, a prolonged QT interval was observed. Genetic studies revealed a mutation in the K(+) channel gene KCNJ2. Over a 4-year follow-up period, recurrence of her arrhythmia occurred twice. The first episode was due to noncompliance and resolved with resumption of flecainide therapy. The second recurrence was associated with a tachycardia-induced cardiomyopathy and resolved when the dose of flecainide was increased from 200 to 300 mg daily. This report suggests that flecainide can be effective in controlling BVT associated with Andersen-Tawil Syndrome and indicates that the left ventricular dysfunction is secondary to the arrhythmia and not due to an associated phenotypic manifestation of the disorder.

  • sudden cardiac death in andersen tawil Syndrome
    Europace, 2007
    Co-Authors: Stefan Peters, Eric Schulzebahr, Susan P Etheridge, Martin Tristanifirouzi
    Abstract:

    Andersen–Tawil Syndrome (ATS) is an autosomal dominant or sporadic disorder characterized by periodic paralysis, dysmorphic features, and ventricular arrhythmias. Although ventricular tachycardia burden is quite high sudden cardiac death in ATS is rare. We describe a case with sudden cardiac death due to electrical storm a few days after ICD implantation in KCNJ2 mutation-negative ATS.

  • andersen tawil Syndrome an ever expanding phenotype
    Heart Rhythm, 2006
    Co-Authors: Martin Tristanifirouzi
    Abstract:

    t s s c c s a n t v A m d c a l i s a m b A t A d t w r e t s b Andersen-Tawil Syndrome is a rare, clinically pleiotropic isorder characterized by ventricular arrhythmias, periodic keletal muscle paralysis, and dysmorphic skeletal feaures. Mutations in KCNJ2, the gene encoding the inwardly ectifying Kir2.1 channel, account for nearly two thirds of eported cases, with the molecular basis of the remaining hird still undefined. Andersen-Tawil Syndrome is fundaentally a disorder of ventricular repolarization manifested y mild QTc interval prolongation but marked prolongation f the QUc interval. Prominent U waves are commonly escribed. Arrhythmias in patients with Andersen-Tawil yndrome include frequent premature ventricular contracions, bigeminy, and polymorphic ventricular tachycardia VT). Typically, VT is nonsustained and bidirectional in ature. Whereas tachycardia burden often is high in subjects ith Andersen-Tawil Syndrome, degeneration into lethal entricular arrhythmias is relatively uncommon. The clinical features of Andersen-Tawil Syndrome repesent a spectrum of phenotypic manifestations encompassng the skeletal muscle and cardiac systems, in addition to raniofacial and skeletal anomalies. A major obstacle in the linical diagnosis of Andersen-Tawil Syndrome is the high egree of phenotypic variability and nonpenetrance. The ull triad of clinical features (ventricular arrhythmias, peridic paralysis, and characteristic dysmorphic features) is resent in 58% to 78% of mutation-positive patients, hereas between 32% and 81% manifest involvement of wo of the three organ systems. Nonpenetrance ranges rom 6% to 20% of mutation-positive individuals. Reently, the Andersen-Tawil Syndrome phenotype was exanded to include several consistent craniofacial features nd dental and skeletal anomalies that were observed in all embers of a small cohort, irrespective of cardiac or neuomuscular findings. In light of the complex clinical manifestations of ndersen-Tawil Syndrome, the report by Schoonderwoerd t al in this issue of Heart Rhythm takes on paramount mportance. Schoonderwoerd et al report a small KCNJ2utation positive family with three affected individuals, two of

Elzbieta Katarzyna Biernacka - One of the best experts on this subject based on the ideXlab platform.

  • natural history and risk stratification in andersen tawil Syndrome type 1
    Journal of the American College of Cardiology, 2020
    Co-Authors: Andrea Mazzanti, Elzbieta Katarzyna Biernacka, Dmitri Guz, Alessandro Trancuccio, Eleonora Pagan, Deni Kukavica, Tekla Chargeishvili, Natalia Olivetti, Luciana Sacilotto, Georgia Sarquellabrugada
    Abstract:

    Abstract Background Andersen-Tawil Syndrome type 1 (ATS1) is a rare arrhythmogenic disorder, caused by loss-of-function mutations in the KCNJ2 gene. We present here the largest cohort of patients with ATS1 with outcome data reported. Objectives This study sought to define the risk of life-threatening arrhythmic events (LAE), identify predictors of such events, and define the efficacy of antiarrhythmic therapy in patients with ATS1. Methods Clinical and genetic data from consecutive patients with ATS1 from 23 centers were entered in a database implemented at ICS Maugeri in Pavia, Italy, and pooled for analysis. Results We enrolled 118 patients with ATS1 from 57 families (age 23 ± 17 years at enrollment). Over a median follow-up of 6.2 years (interquartile range: 2.7 to 16.5 years), 17 patients experienced a first LAE, with a cumulative probability of 7.9% at 5 years. An increased risk of LAE was associated with a history of syncope (hazard ratio [HR]: 4.54; p = 0.02), with the documentation of sustained ventricular tachycardia (HR 9.34; p = 0.001) and with the administration of amiodarone (HR: 268; p  Conclusions Our data demonstrate that the clinical course of patients with ATS1 is characterized by a high rate of LAE. A history of unexplained syncope or of documented sustained ventricular tachycardia is associated with a higher risk of LAE. Amiodarone is proarrhythmic and should be avoided in patients with ATS1.

  • coincidence of andersen tawil Syndrome and marfan Syndrome a case report
    Annals of Noninvasive Electrocardiology, 2019
    Co-Authors: Michalina Krych, Joanna Poninska, Zofia T Bilinska, Rafal Ploski, Elzbieta Katarzyna Biernacka
    Abstract:

    We report on a 44-year-old woman with coincidence of two genetic disorders: Andersen-Tawil Syndrome and Marfan Syndrome. In both, life-threatening arrhythmias could occur. A 44-year-old woman presented acute ascending aortic dissection with aortic arch involvement and chronic thoracic descending and abdominal aortic dissection. Clinical and genetic examination confirmed Marfan Syndrome (MFS) diagnosis. Due to repolarization disorder in ECG and premature ventricular contractions in Holter ECG, the sequencing data were analyzed again and mutation in KCNJ2 gene was identified. The case showed that coincidence of Andersen-Tawil Syndrome (ATS) and MFS did not provoke life-threatening arrhythmias. Complication was rather caused by expression of FBN1 mutation.

  • andersen tawil Syndrome clinical presentation and predictors of symptomatic arrhythmias possible role of polymorphisms k897t in kcnh2 and h558r in scn5a gene
    Journal of Cardiology, 2017
    Co-Authors: Michalina Krych, Charles Antzelevitch, Piotr Kukla, Elzbieta Katarzyna Biernacka, Joanna Poninska, Agnieszka Kosiec, Robert Gajda, Artur Filipecki, Can Hasdemir, Malgorzata Szperl
    Abstract:

    Abstract Background Andersen-Tawil Syndrome (ATS) is rare channelopathy caused by KCNJ2 mutation and probably KCNJ5 . It is characterized by arrhythmias, neurological symptoms, and dysmorphic features. The present study retrospectively examined the characteristics of 11 unrelated families with ATS. Methods This study consisted of 11 probands positive for KCNJ2 variants and 33 family members (mean age 30.0 ± 17.3 years, female n  = 31). Additional genetic screening of 3 LQTS genes ( KCNQ1 , KCNH2 , SCN5A ) was performed in 9 families. Predictors of arrhythmias [premature ventricular beats > 2000/24 h, biventricular and polymorphic ventricular tachycardia (VT)], syncope, and/or cardiac arrest (CA) were evaluated. Results In KCNJ2 mutation carriers vs non-carriers ( n  = 25 vs n  = 19) significant differences were observed in U-wave manifestations in V2–V4, T peak  −  T end duration, QTUc duration ( p n  = 9), in those with arrhythmias and/or syncope and/or CA ( n  = 16) micrognathia ( p  = 0.004), periodic paralysis ( p  = 0.019), palpitation ( p  = 0.005), U-wave n V2–V4 ( p  = 0.049) were more frequent; QTU ( p  = 0.045) and T peak  −  T end ( p  = 0.014) were also longer ( n  = 9). In the subgroup of carriers with syncope and/or cardiac arrest ( n  = 10, 90% women), K897T- KCNH2 polymorphism ( p  = 0.02), periodic paralysis ( p  = 0.004), muscle weakness ( p  = 0.04), palpitations ( p  = 0.04), arrhythmias (biventricular VT, p  = 0.003; polymorphic VT, p  = 0.009) were observed more frequently. T peak  −  T end duration was longer ( p  = 0.007) and the percentage of patients with premature ventricular contraction >2000/24 h was higher ( p  = 0.005). Conclusion A higher risk of arrhythmia, syncope, and/or CA is associated with the presence of micrognathia, periodic paralysis, and prolonged T peak  −  T end time. Our findings suggest that K897T may contribute to the occurrence of syncope.

  • Electrocardiogram in Andersen-Tawil Syndrome. New Electrocardio- graphic Criteria for Diagnosis of Type-1 Andersen-Tawil Syndrome
    2016
    Co-Authors: Piotr Kukla, Elzbieta Katarzyna Biernacka, Adrian Baranchuk, Marek Jastrzębski, Michalina Jagodzinska
    Abstract:

    Abstract: Andersen- Tawil Syndrome (ATS) is an autosomal- dominant or sporadic disorder characterized by ventricular arrhythmias, periodic paralysis, and distinctive facial and skeletal dysmorphism. Mutations in KCNJ2, which encodes the α-subunit of the potassium channel Kir2.1, were identified in patients with ATS. This genotype has been designated as type-1 ATS (ATS1). KCNJ2 mutations are detectable in up to 60 % of patients with ATS. Cardiac manifestations of ATS include frequent premature ventricular contractions (PVC), Q-U interval prolongation, prominent U-waves, and a special type of polymorphic ventricular tachycardia (PMVT) called bidirectional ventricular tachycardia (BiVT). The presence of frequent PVCs at rest are helpful in distinguishing ATS from typical catecholaminergic polymorphic ventricular tachycar-dia (CPVT). In typical CPVT, rapid PMVT and BiVT usually manifest during or after exercising. Additionally, CPVT or torsade de pointes in LQTS are faster, very symptomatic causing syncope or often deteriorate into VF resulting in sudden cardiac death. PVCs at rest are quite frequent in ATS1 patients, however, in LQTS patients, PVCs and asymptomatic VT are uncommon which also contributes to differentiating them. The article describes the new electrocardiographic criteria proposed for diagnosis of type-1 Andersen-Tawil Syndrome. A differential diagnosis between Andersen-Tawil Syndrome, the catecholamine polymorphic ventiruclar tachycardia and long QT Syndrome is depicted. Special attention is paid on the repolarization abnormalities, QT interval and the patho

  • coexistence of andersen tawil Syndrome with polymorphisms in herg1 gene k897t and scn5a gene h558r in one family
    Annals of Noninvasive Electrocardiology, 2016
    Co-Authors: Michalina Jagodzinska, Piotr Kukla, Joanna Poninska, Malgorzata Szperl, Agnieszka Kosiec, Robert Gajda, Elzbieta Katarzyna Biernacka
    Abstract:

    Background Andersen–Tawil Syndrome (ATS) is a channelopathy caused by mutations in KCNJ2 gene. It is characterized by symptoms of ventricular arrhythmias, periodic paralysis or muscle weakness, and dysmorphic features. ATS can present with the triad of symptoms, any combination or none of them. Risk factors for dangerous arrhythmias are unknown. The study assessed the impact of K897T polymorphism in hERG1 gene and H558R polymorphism in SCN5A gene coexisting with R218Q mutation in KCNJ2 in one family on clinical manifestation. Methods Family members underwent clinical assessment, ECG and genotyping. Holter monitoring was performed in mutation carriers and additionally in one family member with no mutation, but with K897T polymorphism. Results Proband with ATS mutation, K897T and H558R polymorphisms and proband's sister with ATS mutation and K897T polymorphism presented following symptoms: loss of consciousness, bidirectional and polymorphic ventricular tachycardia and about 5000 ventricular extrasystoles. Symptoms presented by the member with only the ATS mutation and by member with ATS mutation and H558R polymorphism were not as severe. U wave appeared in all examined family members regardless of the mutation presence. Studied individuals with ATS mutation had the T-peak–U-peak interval longer than 200 ms. In all ATS mutation carriers it was longer than in family members with no mutation. T-peak–T-end interval was the longest (>120 ms) in members with coexisting mutation and K897T polymorphism. Conclusion ATS severity possibly depends on other genes’ polymorphisms. In the presented family, it could depend on the presence of K897T polymorphism in hERG1.

Minoru Horie - One of the best experts on this subject based on the ideXlab platform.

  • clinical and neurophysiological variability in andersen tawil Syndrome
    Muscle & Nerve, 2019
    Co-Authors: Norito Kokubun, Minoru Horie, Reika Aoki, Takahide Nagashima, Tomoko Komagamine, Yusuke Kuroda, Koichi Hirata
    Abstract:

    Introduction Andersen-Tawil Syndrome (ATS) is characterized by a triad of periodic paralysis, ventricular arrhythmias, and dysmorphism. However, patients often lack one or more of these features. Methods Clinical and neurophysiological features were reviewed of five members in two families with heterozygous mutations in KCNJ2 (R218Q and R67W). Results Only one patient had all features of the triad of ATS. One patient had low-set ears, and the others had minor anomalies. Bidirectional ventricular tachycardias were seen in two patients. Two patients (R67W) never had episodes of paralysis. The long exercise test was abnormal in three patients with episodes of paralysis, but normal in two without paralytic episodes. Discussion ATS patients without skeletal muscle symptoms can have normal neurophysiological examinations. They can show variability in phenotype or the severity of arrhythmias. Such variability among patients who share the same gene mutations may result in underdiagnosis of ATS.

  • Address for correspondence:
    2016
    Co-Authors: Hiromi Kimura, Md Jun Zhou, Mihoko Kawamura, Md Hideki Itoh, Minoru Horie
    Abstract:

    2 Background- Mutations of KCNJ2, the gene encoding the human inward rectifier potassium channel Kir2.1, cause Andersen-Tawil Syndrome (ATS), a disease exhibiting ventricular arrhythmia, periodic paralysis and dysmorphic features. However, some KCNJ2 mutation carriers lack the ATS triad and sometimes share the phenotype of catecholaminergic polymorphic ventricular tachycardia (CPVT). We investigated clinical and biophysical characteristics of KCNJ2 mutation carriers with “atypical ATS”. Methods and Results- Mutational analyses of KCNJ2 were performed in 57 unrelated probands showing typical (2 ATS features) and atypical (only one of the ATS features or CPVT) ATS. We identified 24 mutation carriers. Mutation-positive rates were: 75 % (15/20) in typical ATS, 71% (5/7) in cardiac phenotype alone, 100 % (2/2) in periodic paralysis and 7 % (2/28) in CPVT. W

  • mosaic kcnj2 mutation in andersen tawil Syndrome targeted deep sequencing is useful for the detection of mosaicism
    Clinical Genetics, 2015
    Co-Authors: Seiko Ohno, Hiromi Kimura, Hideki Itoh, Takeru Makiyama, Kanae Hasegawa, Y Yoshida, Minoru Horie
    Abstract:

    Andersen-Tawil Syndrome (ATS) is an inherited disease characterized by ventricular arrhythmias, periodic paralysis, and dysmorphic features. It results from a heterozygous mutation of KCNJ2, but little is known about mosaicism in ATS. We performed genetic analysis of KCNJ2 in 32 ATS probands and their family members and identified KCNJ2 mutations in 25 probands, 20 families who underwent extensive genetic testing. These tests revealed that seven probands carried de novo mutations while 13 carried inherited mutations from their parents. We then specifically assessed a single proband and the respective family. The proband was a 9 year old girl who fulfilled the ATS triad and carried an insertion mutation (p.75_76insThr). We determined that the proband's mother carried a somatic mosaicism and that the proband's younger brother also carried the ATS phenotype with the same insertion mutation. The mother, who exhibited mosaicism, was asymptomatic, although she exhibited Q(T)U prolongation. Mutant allele frequency was 11% as per TA cloning and 17.3% as per targeted deep sequencing. Our observations suggest that targeted deep sequencing is useful for the detection of mosaicism and that the detection of mosaic mutations in parents of apparently sporadic ATS patients can help in the process of genetic counseling.

  • abstract 12704 the prognosis of andersen tawil Syndrome is not so benign as ever thought
    Circulation, 2014
    Co-Authors: Hiromi Kimura, Seiko Ohno, Yusuke Fujii, Mari Ichikawa, Hideki Itoh, Takeru Makiyama, Megumi Fukuyama, Kouichi Kato, Minoru Horie
    Abstract:

    Rationale: Andersen-Tawil Syndrome (ATS) represents ventricular arrhythmia with abnormal U wave, periodic paralysis, and dysmorphysm, resulting from reduction of IK1 current due to KCNJ2 gene mutation. There are few reports about prognosis of ATS. In 2013, a French group reported that the prognosis of ATS was relatively benign under treatment. However, some our KCNJ2-positive patients show aborted cardiac arrest in their adult phase. Here, we examined long-term outcome in Japanese KCNJ2-positive ATS cohort. Methods and Results: In 32 probands with at least one of ATS features, we screened KCNJ2, KCNQ1, KCNH2, and SCN5A genes. Excluding 2 compound mutations and 1 double mutation cases, we found 14 KCNJ2 mutations in 23 probands (71%). We sent the inquiry sheet to all the attending physicians of probands and collected probands’ symptoms, ECGs, and history of cardiac events. For the average follow-up period of 79 months, four of 23 probands (17%) experienced syncope. Twenty-two of 23 (96%) patients showed ve...

  • electrocardiographic features in andersen tawil Syndrome patients with kcnj2 mutations characteristic t u wave patterns predict the kcnj2 genotype
    Circulation, 2005
    Co-Authors: Rabi Tawil, Alfred L George, Woodrow D Benson, Li Zhang, Martin Tristanifirouzi, Louis J Ptacek, Peter J Schwartz, Minoru Horie, Gregor Andelfinger
    Abstract:

    Background— The ECG features of Andersen-Tawil Syndrome (ATS) patients with KCNJ2 mutations (ATS1) have not been systematically assessed. This study aimed to define ECG features of KCNJ2 mutation carriers, to determine whether characteristic T-U–wave patterns exist, and to establish whether T-U patterns predict the ATS1 genotype. Methods and Results— In phase I, evaluation of T-U morphology in ECGs of 39 KCNJ2 mutation carriers identified characteristic T-U patterns: prolonged terminal T downslope, wide T-U junction, and biphasic and enlarged U waves. In phase II, ATS1 genotype prediction by T-U pattern was evaluated in the next 147 ECGs (57 other KCNJ2 mutation carriers, 61 unaffected family members, and 29 ATS patients without KCNJ2 mutations), with a sensitivity of 84% and specificity of 97%. Characteristic T-U patterns were present in 91% (87/96), in whom an enlarged U wave was predominant (73%). In phase III, QTc, QUc, and T- and U-wave duration/amplitude were compared in the 96 ATS1, 29 non-KCNJ2 AT...

Charles Antzelevitch - One of the best experts on this subject based on the ideXlab platform.

  • andersen tawil Syndrome clinical presentation and predictors of symptomatic arrhythmias possible role of polymorphisms k897t in kcnh2 and h558r in scn5a gene
    Journal of Cardiology, 2017
    Co-Authors: Michalina Krych, Charles Antzelevitch, Piotr Kukla, Elzbieta Katarzyna Biernacka, Joanna Poninska, Agnieszka Kosiec, Robert Gajda, Artur Filipecki, Can Hasdemir, Malgorzata Szperl
    Abstract:

    Abstract Background Andersen-Tawil Syndrome (ATS) is rare channelopathy caused by KCNJ2 mutation and probably KCNJ5 . It is characterized by arrhythmias, neurological symptoms, and dysmorphic features. The present study retrospectively examined the characteristics of 11 unrelated families with ATS. Methods This study consisted of 11 probands positive for KCNJ2 variants and 33 family members (mean age 30.0 ± 17.3 years, female n  = 31). Additional genetic screening of 3 LQTS genes ( KCNQ1 , KCNH2 , SCN5A ) was performed in 9 families. Predictors of arrhythmias [premature ventricular beats > 2000/24 h, biventricular and polymorphic ventricular tachycardia (VT)], syncope, and/or cardiac arrest (CA) were evaluated. Results In KCNJ2 mutation carriers vs non-carriers ( n  = 25 vs n  = 19) significant differences were observed in U-wave manifestations in V2–V4, T peak  −  T end duration, QTUc duration ( p n  = 9), in those with arrhythmias and/or syncope and/or CA ( n  = 16) micrognathia ( p  = 0.004), periodic paralysis ( p  = 0.019), palpitation ( p  = 0.005), U-wave n V2–V4 ( p  = 0.049) were more frequent; QTU ( p  = 0.045) and T peak  −  T end ( p  = 0.014) were also longer ( n  = 9). In the subgroup of carriers with syncope and/or cardiac arrest ( n  = 10, 90% women), K897T- KCNH2 polymorphism ( p  = 0.02), periodic paralysis ( p  = 0.004), muscle weakness ( p  = 0.04), palpitations ( p  = 0.04), arrhythmias (biventricular VT, p  = 0.003; polymorphic VT, p  = 0.009) were observed more frequently. T peak  −  T end duration was longer ( p  = 0.007) and the percentage of patients with premature ventricular contraction >2000/24 h was higher ( p  = 0.005). Conclusion A higher risk of arrhythmia, syncope, and/or CA is associated with the presence of micrognathia, periodic paralysis, and prolonged T peak  −  T end time. Our findings suggest that K897T may contribute to the occurrence of syncope.

  • biophysical and molecular characterization of a novel de novo kcnj2 mutation associated with andersen tawil Syndrome and catecholaminergic polymorphic ventricular tachycardia mimicry
    Circulation-cardiovascular Genetics, 2011
    Co-Authors: Hector Barajasmartinez, Gustavo Ontiveros, Gabriel Caceres, Mayurika Desai, Elena Burashnikov, Jorge Scaglione, Charles Antzelevitch
    Abstract:

    Background— Mutations in KCNJ2 , the gene encoding the human inward rectifier potassium channel Kir2.1 (IK1 or IKir2.1), have been identified in Andersen-Tawil Syndrome. Andersen-Tawil Syndrome is a multisystem inherited disease exhibiting periodic paralysis, cardiac arrhythmias, and dysmorphic features at times mimicking catecholaminergic polymorphic ventricular tachycardia. Methods and Results— Our proband displayed dysmorphic features including micrognathia, clinodactyly, and syndactyly and exhibited multiform extrasystoles and bidirectional ventricular tachycardia both at rest and during exercise testing. The patient's symptoms continued after administration of nadolol but subsided after treatment with flecainide. Molecular genetic screening revealed a novel heterozygous mutation (c.779G>C/p.R260P) in KCNJ2 . Whole-cell patch-clamp studies conducted in TSA201 cells transfected with wild-type human KCNJ2 cDNA (WT- KCNJ2 ) yielded robust IKir2.1 but no measurable current in cells expressing the R260P mutant. Coexpression of WT and R260P- KCNJ2 (heterozygous expression) yielded a markedly reduced inward IKir2.1 compared with WT alone (−36.5±9.8 pA/pF versus −143.5±11.4 pA/pF, n=8 for both, P <0.001, respectively, at −90 mV), indicating a strong dominant negative effect of the mutant. The outward component of IKir2.1 measured at −50 mV was also markedly reduced with the heterozygous expression versus WT (0.52±5.5 pA/pF versus 23.4±6.7 pA/pF, n=8 for both, P <0.001, respectively). Immunocytochemical analysis indicates that impaired trafficking of R260P- KCNJ2 channels. Conclusions— We report a novel de novo KCNJ2 mutation associated with classic phenotypic features of Andersen-Tawil Syndrome and catecholaminergic polymorphic ventricular tachycardia mimicry. The R260P mutation produces a strong dominant negative effect leading to marked suppression of IK1 secondary to a trafficking defect.

  • biophysical characterization of a novel kcnj2 mutation associated with andersen tawil Syndrome and cpvt mimicry
    Biophysical Journal, 2009
    Co-Authors: Hector Barajasmartinez, Gustavo Ontiveros, Gabriel Caceres, Elena Burashnikov, Jorge Scaglione, Charles Antzelevitch
    Abstract:

    Mutations in KCNJ2, the gene encoding the human inward rectifier potassium channel Kir2.1 (IK1), have been identified in Andersen-Tawil Syndrome (ATS). ATS is a multisystem inherited disease exhibiting periodic paralysis, cardiac arrhythmias, and dysmorphic features at times mimicking catecholaminergic polymorphic ventricular tachycardia (CPVT). In this study, we identified a young female presenting with frequent ventricular extrasystoles and non-sustained polymorphic ventricular tachycardia (VT), bi-directional VT, syncope, and mild QTc prolongation. The proband displayed dysmorphic features including micrognatia, clinodactylia and syndactyly. The patient's symptoms continued following administration of propranolol, but subsided after treatment with flecainide. Molecular genetic screening revealed a novel heterozygous mutation (c.779G>C/p R260P) in KCNJ2. Whole-cell patch-clamp studies conducted in TSA201 cells transfected with wild type human KCNJ2 cDNA (WT-KCNJ2) yielded robust IK1, but no measurable current in cells expressing the R260P mutant. Co-expression of WT and R260P-KCNJ2 (heterozygous expression) yielded a markedly reduced inward IK1 compared with WT alone (-36.5±9.8 pA/pF vs. -143.5±11.4 pA/pF, n=8, p>0.001, respectively at -90 mV) indicating a strong dominant negative effect of the mutant. The outward component of IK1 measured at -50 mV was also markedly reduced with the heterozygous expression vs. WT (0.52±5.5 pA/pF vs. 23.4±6.7 pA/pF, n=8, p>0.001, respectively). Conclusion: We report a novel KCNJ2 mutation associated with classical phenotypic features of Andersen-Tawil Syndrome and CPVT mimicry. The R260P mutation produced a strong dominant negative effect leading to marked suppression of the inward rectifier potassium current.

  • cellular basis for electrocardiographic and arrhythmic manifestations of andersen tawil Syndrome lqt7
    Heart Rhythm, 2006
    Co-Authors: Masato Tsuboi, Charles Antzelevitch
    Abstract:

    Background Andersen-Tawil Syndrome, a skeletal muscle Syndrome associated with periodic paralysis and long QT intervals on the ECG, has been linked to defects in KCNJ2, the gene encoding for the inward rectifier potassium channel (I K1 .) Objectives The purpose of this study was to examine the cellular mechanisms underlying the ECG and arrhythmic manifestations of Andersen-Tawil Syndrome. Methods To investigate the effects of KCNJ2 loss-of-function mutations responsible for Andersen-Tawil Syndrome, we used barium chloride (BaCl 2 ) to inhibit I K1 in arterially perfused wedge preparation. Transmembrane action potentials (APs) were simultaneously recorded from endocardial, midmyocardial, and epicardial cells, together with a transmural ECG. Results BaCl 2 (1 to 30 μM) produced a concentration-dependent prolongation of the QT interval, secondary to a homogeneous prolongation of AP duration of the three cell types. QT interval was prolonged without an increase in transmural dispersion of repolarization (TDR). Low extracellular potassium (2.0 mM), isoproterenol (20–50 nM), and an abrupt increase in temperature (36°C–39°C) in the presence of 10 μM BaCl 2 did not significantly increase TDR but increased ectopic extrasystolic activity. Early afterdepolarizations were not observed under any condition. Spontaneous torsades de pointes arrhythmias were never observed, nor could they be induced with programmed electrical stimulation under any of the conditions studied. Conclusion Our results provide an understanding of why QT prolongation associated with Andersen-Tawil Syndrome is relatively benign in the clinic and provide further support for the hypothesis that the increase in TDR, rather than QT interval, is responsible for development of torsades de pointes.

Louis J Ptacek - One of the best experts on this subject based on the ideXlab platform.

  • report of a turkish girl with andersen tawil Syndrome
    Journal of pediatric neurology, 2015
    Co-Authors: Huseyin Caksen, Louis J Ptacek, Abdurrahman Uner, Mehmet Erol, Omer Anlar, Cahide Yilmaz, Ahmet Sami Guven
    Abstract:

    The case is a 9-year-old girl with a history of syncope attacks for 6 years and recurrent paraplegia attacks for 1.5 years. She was diagnosed with epilepsy and was given valproate for the attacks, but no improvement was noted. Because of her paraplegia attacks, lasting between a few hours and 3 days, abnormal findings she was diagnosed with conversion. Her prenatal, natal and postnatal history was unremarkable, and her school performance was high. There was a close consanguinity between the parents. She had four healthy sibs. Her mother, maternal uncle and maternal grandmother had intermittent fatigue, numbness on the extremities. On physical examination, she had mild elongated face and dysmorphic changes on the hands. Muscle strength was normal on the upper extremities, but no muscle activity was noted on the lower extremities. She also had no response to touch and pain stimuli on the lower extremities. On laboratory investigation, serum electrolytes including potassium level, renal and liver function tests were normal. Glomerul filtration rate was 59 mL/min/m 2 . QTc interval was mild prolonged (0.45 seconds). Electromyographic examination was unremarkable. On DNA mutation analysis, no mutation of KCJN2 gene coding for Kir 2.1 protein was diagnosed. Her mother had normal serum electrolytes, but had prolonged QTc interval (0.46 seconds). Her father was completely normal for serum electrolytes and electrocardiographic examination. Unfortunately, maternal uncle and grandmother could not be examined. Based on the clinical and laboratory abnormalities she was diagnosed with Andersen-Tawil Syndrome and given potassium supplementation. Her paraplegia and syncope attacks were markedly decreased after initiating potassium therapy. Now, she is in the 3rd year of follow-up. She is continued to use potassium and her paraplegia and syncope attacks noted only one attack a 2-3 months.

  • andersen tawil Syndrome definition of a neurocognitive phenotype
    Neurology, 2006
    Co-Authors: G Yoon, Lovingly C Quitania, Joel H Kramer, Bruce L Miller, Louis J Ptacek
    Abstract:

    Background: The Andersen–Tawil Syndrome (ATS) is a potassium ion channelopathy caused by mutations in the KCNJ2 gene. It is characterized by periodic paralysis, cardiac arrhythmias, and distinctive features; the effect of KCNJ2 mutations on the CNS has never been studied. Objective: To define a potential CNS phenotype in ATS using standardized methods. Methods: Ten subjects with KCNJ2 mutations and their unaffected siblings were evaluated at the University of California San Francisco General Clinical Research Center. A comprehensive battery of neurocognitive tests was administered to ATS subjects and their unaffected siblings, followed by pairwise analysis of the resultant differences in scores. An EEG was obtained for all ATS subjects. Results: There was no EEG evidence of subclinical seizure activity in any subject. ATS subjects universally had more school difficulties than their siblings, despite similar IQ between the two groups. On formal neurocognitive testing, there was no difference between ATS subjects and their siblings on tests of verbal and visual memory. Assessment of executive functioning revealed ATS subjects scored 1.93 points lower than their siblings on tests of Design Fluency (95% CI −3.46, 0.01; p = 0.052) and made 1.9 more errors (95% CI 0.46, 2.54; p = 0.005). Subjects with ATS scored an average of 5 points lower than their siblings on tests of matrix reasoning (95% CI −8.67, −1.33; p = 0.008). On tests of general ability, ATS subjects achieved much lower scores than their siblings, with an average difference of 9.13 points for reading (95% CI −12.46, 3.21; p = 0.056) and 23.4 points for mathematics (95% CI −42.53, −4.22; p = 0.017). Conclusion: Mutations in KCNJ2 are associated with a distinct neurocognitive phenotype, characterized by deficits in executive function and abstract reasoning.

  • andersen tawil Syndrome prospective cohort analysis and expansion of the phenotype
    American Journal of Medical Genetics Part A, 2006
    Co-Authors: G Yoon, Martin Tristanifirouzi, Susan P Etheridge, Snehlata Oberoi, Lovingly C Quitania, Joel H Kramer, Bruce L Miller, Louis J Ptacek
    Abstract:

    Andersen-Tawil Syndrome (ATS) is an autosomal dominant multisystem disorder characterized by developmental, cardiac, and neuromuscular abnormalities. Approximately 70% of patients have mutations in KCNJ2, resulting in dysfunction of the inward-rectifying potassium channel Kir2.1. Variable expression complicates the diagnosis of ATS, which in many cases, is not made until years after the first recognized symptom. To better define the distinctive clinical features of ATS and facilitate earlier diagnosis, we conducted a prospective, standardized evaluation of 10 subjects with confirmed KCNJ2 mutations. Detailed anthropometric, neurological, and cardiac evaluations were performed. Using this approach, we identified novel skeletal and dental findings and proposed additional diagnostic criteria for ATS dysmorphology.

  • electrocardiographic features in andersen tawil Syndrome patients with kcnj2 mutations characteristic t u wave patterns predict the kcnj2 genotype
    Circulation, 2005
    Co-Authors: Rabi Tawil, Alfred L George, Woodrow D Benson, Li Zhang, Martin Tristanifirouzi, Louis J Ptacek, Peter J Schwartz, Minoru Horie, Gregor Andelfinger
    Abstract:

    Background— The ECG features of Andersen-Tawil Syndrome (ATS) patients with KCNJ2 mutations (ATS1) have not been systematically assessed. This study aimed to define ECG features of KCNJ2 mutation carriers, to determine whether characteristic T-U–wave patterns exist, and to establish whether T-U patterns predict the ATS1 genotype. Methods and Results— In phase I, evaluation of T-U morphology in ECGs of 39 KCNJ2 mutation carriers identified characteristic T-U patterns: prolonged terminal T downslope, wide T-U junction, and biphasic and enlarged U waves. In phase II, ATS1 genotype prediction by T-U pattern was evaluated in the next 147 ECGs (57 other KCNJ2 mutation carriers, 61 unaffected family members, and 29 ATS patients without KCNJ2 mutations), with a sensitivity of 84% and specificity of 97%. Characteristic T-U patterns were present in 91% (87/96), in whom an enlarged U wave was predominant (73%). In phase III, QTc, QUc, and T- and U-wave duration/amplitude were compared in the 96 ATS1, 29 non-KCNJ2 AT...

  • andersen tawil Syndrome a model of clinical variability pleiotropy and genetic heterogeneity
    Annals of Medicine, 2004
    Co-Authors: Matthew R Donaldson, Grace Yoon, Louis J Ptacek
    Abstract:

    Due to its varied and variable phenotypes, Andersen‐Tawil Syndrome (ATS) holds a unique place in the field of channelopathies. Patients with ATS typically present with the triad of periodic paralysis, cardiac arrhythmias, and developmental dysmorphisms. Although penetrance of ATS is high, disease expression and severity are remarkably variable. Mutations in KCNJ2 are the primary cause of ATS with 21 mutations discovered in 30 families. These mutations affect channel function through heterogeneous mechanisms, including reduced PIP 2 ‐related channel activation and altered pore function. Aside from KCNJ2‐based ATS, the genetic basis of this disease in nearly 40% of cases is unknown. Other ATS genes likely share a common pathway or function with Kir2.1 or facilitate the activity of this ion channel. In this review, we explore hypotheses explaining the pathogenesis, expression, and variability of ATS.