Andersen-Tawil Syndrome Research Articles

Oral verapamil effectively suppressed complex ventricular arrhythmias and unmasked U waves in a patient with Andersen-Tawil syndrome

Andersen-Tawil syndrome (ATS) is a rare, heterogeneous, autosomal dominant, or sporadic disorder characterized by the clinical triad of periodic paralysis, dysmorphic features, and ventricular arrhythmias such as bidirectional ventricular tachycardia (BVT). We present a case of an elderly patient with ATS whose symptomatic ventricular arrhythmias including BVT were effectively suppressed by oral verapamil therapy.

Coexistent manifestations of the Andersen-Tawil and Brugada syndromes

The Andersen-Tawil syndrome (ATS) is a rare inherited disorder characterized by periodic paralysis, ventricular arrhythmias, skeletal developmental abnormalities, and in most cases, prolongation of the QT interval (or more correctly, the QU interval). The Brugada syndrome (BS) similarly is an inherited disorder manifested by the unique electrocardiographic (ECG) abnormality of ST-segment elevation in leads V1 and V2, ventricular arrhythmias, and sudden cardiac death. This report details an unusual patient with manifestations of both syndromes, who was treated by the implantation of a defibrillator (implanted cardioverter/defibrillator).

Prevalence of early-onset atrial fibrillation in congenital long QT syndrome

The prevalence of atrial fibrillation (AF) in the young (age <50 years) is 0.1%, or 1:1,000 persons. Mutations in KCNQ1-, KCNH2-, and KCNA5-encoded potassium channels and SCN5A-encoded sodium channels have been reported in familial AF. A mechanism of atrial torsade has been suggested to occur in patients with congenital long QT syndrome (LQTS). The purpose of this study was to determine the prevalence of AF in patients with congenital LQTS. History of documented AF was sought from two independent cohorts. One cohort consisted of 252 consecutive patients (146 females and 106 males, average age at diagnosis 23 +/- 16 years, QTc 465 +/- 51 ms) with genetically proven LQTS seen at Mayo's LQTS Clinic. The second cohort consisted of 205 consecutive patients (133 females and 72 males, average age at testing 23 +/- 16 years, QTc 479 +/- 51 ms) with a positive FAMILION genetic test (PGxHealth) for LQTS. Early-onset AF was documented in 8 (1.7%) of 457 patients, including 6 (2.4%) of 252 patients seen at Mayo and 2 (1%) of 205 patients with a positive FAMILION test. Five (2.4%) of 211 patients with LQT1-susceptibility mutations had documented AF, compared to 0 of 174 patients with LQT2, 1 of 59 patients with LQT3, 1 of 1 patient with Andersen-Tawil syndrome, and 1 of 34 patients with multiple mutations. The average age at diagnosis of AF of the six patients evaluated at Mayo was 24.3 years (range 4-46 years). Early-onset AF (age <50 years) was significantly more common in patients with LQTS compared to population-based prevalence statistics (P <.001, relative risk 17.5). Compared to the background prevalence of 0.1%, early-onset AF was observed in almost 2% of patients with genetically proven LQTS and should be viewed as an uncommon but possible LQT-related dysrhythmia. Clinical complaints of palpitations warrant thorough assessment in patients with LQTS.

Calcium channel blocker and adenosine triphosphate terminate bidirectional ventricular tachycardia in a patient with Andersen-Tawil syndrome

Calcium channel blocker and adenosine triphosphate terminate bidirectional ventricular tachycardia in a patient with Andersen-Tawil syndrome

Primary periodic paralyses

To review the current knowledge about primary periodic paralyses (PPs). Periodic paralyses are a heterogeneous group of disorders, clinically characterized by episodes of flaccid muscle weakness, occurring at irregular intervals. PPs are divided into primary (hereditary) and secondary (acquired) forms of which the secondary PPs are much more common than the primary PPs. Primary PPs are due to mutations in genes encoding for subunits of channel proteins of the skeletal muscle membrane, such as the muscular sodium, potassium or calcium channels, or the SCL4A1 protein. Primary PPs include entities such as hyperkalemic PP, hypokalemic PP, paramyotonia congenita von Eulenburg, Andersen's syndrome, thyrotoxic PP, distal renal tubular acidosis, X-linked episodic muscle weakness syndrome and congenital myasthenic syndromes. Attacks of weakness or myotonia may be triggered or enhanced by vigorous exercise, cold, potassium-rich food, emotional stress, drugs such as glucocorticosteroids, insulin or diuretics, or pregnancy. Depending on the pathomechanism, episodes of weakness may respond to mild exercise, ingestion of potassium, carbohydrates, salbutamol, calcium gluconate, thiazide diuretics, carboanhydrase inhibitors, such as acetazolamide or dichlorphenamine, and episodes may be prevented by avoidance of potassium-rich food, or drugs, which increase serum potassium. This review presents and discusses current knowledge and recent advances in the etiology, molecular genetics, genotype-phenotype correlations, pathogenesis, diagnosis and treatment of primary PPs.

Flecainide Suppresses Bidirectional Ventricular Tachycardia and Reverses Tachycardia‐Induced Cardiomyopathy in Andersen‐Tawil Syndrome

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.

Abstract 2257: KCNJ2 Mutations in Patients Referred for Catecholaminergic Polymorphic Ventricular Tachycardia Gene Screening

Background : Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by adrenergically mediated polymorphic or bidirectional ventricular tachycardia (BVT). Andersen-Tawil syndrome (ATS1), which are mainly caused by KCNJ2 mutations, phenocopies CPVT and may manifest the typical adrenergically mediated BVT. The purpose of this study was assess whether patients (pts) lacking periodic paralysis typical of ATS1 and diagnosed as CPVT because of BVT carry KCNJ2 mutations. Methods and Results : Mutational analysis of KCNJ2 was performed in 23 RyR2 and CASQ2 genotype-negative CPVT pts with normal QT interval. Two novel missense mutations (S220I and T305I) were identified. Mutations were absent in &gt;400 reference alleles. Both of the pts present exercise or isoproterenol induced BVT, baseline ECG with prominent U wave and mild facial abnormalities. In vitro characterization showed that no current is detectable when S220I and T305I mutants clones are expressed; on the contrary co-expression of WT and mutant KCNJ2 to mimic heterozygosis present in patients, caused significant dominant negative effect (see figure ). Confocal laser microscopy revealed normal sarcolemmal localization of the mutant channels and of the heterozygous channels. Conclusions : KCNJ2 mutation with loss of function are present in a minority of pts with clinical diagnosis of CPVT. Given the limited number of CPVT pts with KCNJ2 mutations it is impossible to determine whether their prognosis is identical to that of RyR2 and CASQ2 related CPVT. Screening of KCNJ2 should be considered in CPVT pts without mutations in RyR2 and CASQ2 genes.

Exaggerated Mg2+ Inhibition of KCNJ2 as a Consequence of Reduced PIP2 Sensitivity in Andersen Syndrome

Andersen syndrome is an autosomal dominant disorder characterized by cardiac arrhythmias, periodic paralysis and dysmorphic features. Many Andersen syndrome cases have been associated with loss-of-function mutations in the inward rectifier K+ channel Kir2.1 encoded by KCNJ2. Using engineered concatenated tetrameric channels we determined the mechanism for dominant loss-of-function associated with a trafficking-competent missense mutation, Kir2.1-T74A. This mutation alters a conserved threonine residue in an N-terminal domain analogous to the slide helix identified in the structure of a bacterial inward rectifier. Incorporation of a single mutant subunit in channel tetramers was sufficient to cause a selective impairment of whole-cell outward current, but no difference in the level of inward current compared with wild-type (WT) tetramers. The presence of two mutant subunits resulted in greatly reduced outward and impaired inward currents. Experiments using excised inside-out membrane patches revealed that tetramers with one mutant subunit exhibited increased Mg2+ inhibition. Additional experiments demonstrated that concatenated tetramers containing one T74A subunit had reduced PIP2 sensitivity, and that outward current carried by mutant tetramers could be restored by addition of PIP2 in the absence of Mg2+. Our results are consistent with the involvement of the Kir2.1 N-terminus in PIP2 modulation of channel activity and support the existence of an inverse relationship between PIP2 sensitivity and Mg2+ inhibition of Kir2.1 channels. Our data also indicate that a single mutant subunit is sufficient to explain dominant-negative behavior of Kir2.1-T74A in Andersen syndrome.

T75M-KCNJ2 mutation causing Andersen–Tawil syndrome enhances inward rectification by changing Mg 2+ sensitivity

Andersen–Tawil syndrome (ATS) is a multisystem inherited disease exhibiting periodic paralysis, cardiac arrhythmias, and dysmorphic features. In this study, we characterized the KCNJ2 channels with an ATS mutation (T75M) which is associated with cardiac phenotypes of bi-directional ventricular tachycardia, syncope, and QT c prolongation. Confocal imaging of GFP-KCNJ2 fusion proteins showed that the T75M mutation impaired membrane localization of the channel protein, which was restored by co-expression of WT channels with T75M channels. Whole-cell patch-clamp experiments in CHO-K1 cells showed that the T75M mutation produced a loss-of-function of the channel. When both WT and the T75M were co-expressed, the T75M mutation showed dominant-negative effects on inward rectifier K + current densities, with prominent suppression of outward currents at potentials between 0 mV and + 80 mV over the E K. Inside-out patch experiments in HEK293T cells revealed that co-expression of WT and the T75M channels enhanced voltage-dependent block of the channels by internal Mg 2+, resulting in enhanced inward rectification at potentials 50 mV more positive than the E K. We suggest that the T75M mutation causes dominant-negative suppression of the co-expressed WT KCNJ2 channels. In addition, the T75M mutation caused alteration of gating kinetics of the mutated KCNJ2 channels, i.e., increased sensitivity to intracellular Mg 2+ and resultant enhancement of inward rectification. The data presented suggest that the mutation may influence clinical features, but it does not directly show this.

Impaired interaction between the slide helix and the C-terminus of Kir2.1: A novel mechanism of Andersen syndrome

Andersen syndrome (AS) is a rare genetic disease caused by mutations of the potassium channel Kir2.1 (KCNJ2). We identified two unrelated patients with mutations in the slide helix of Kir2.1 leading to AS. The functional consequences of these two mutations, Y68D and D78Y, were studied and compared with previously reported slide helix mutations. Channel function and surface expression were studied by voltage clamp recordings and a chemiluminescence assay in Xenopus laevis oocytes and by patch clamp recordings and fluorescence microscopy in HEK293 cells. In addition, a phosphatidylinositol bisphosphate (PIP(2)) binding assay and a yeast-two-hybrid assay were used to characterize the molecular mechanisms by which slide helix mutations cause AS. Neither mutant channel produced any current, but both had dominant negative effects on Kir2.2, Kir2.3, and Kir2.4 channels. We show that Y68D, D78Y, and previously reported AS mutations are clustered on the hydrophilic, cytosolic side of the slide helix and traffic normally to the plasma membrane. The in vitro lipid binding assay indicated that Y68D or D78Y N-terminal peptides bind PIP(2) similar to wild-type peptides. Yeast-two-hybrid assays showed that AS-associated mutations disturb the interaction between the slide helix and the C-terminal domain of the channel protein. Our experiments indicate a new disease-causing mechanism independent of trafficking and PIP(2) binding defects. Our findings suggest that the hydrophilic side of the slide helix interacts with a specific domain of the C-terminus facing the membrane. This interaction, which may be required for normal gating both in homomeric and heteromeric Kir2 channels, is disturbed by several mutations causing AS.

Mechanism of U wave and polymorphic ventricular tachycardia in a canine tissue model of Andersen–Tawil syndrome

Andersen-Tawil syndrome (ATS) is a channelopathy affecting inward rectifier potassium I(K1) with QT prolongation, large U waves, and frequent ventricular tachycardia (VT). Although ATS is clinically defined and genetically identified, its electrophysiological mechanism is still unclear, and thus, was the subject of the current study. We replicated the major electrophysiological features of ATS with cesium chloride (CsCl, at I(K1) blockade concentration of 5-10 mmol/l) in 23 isolated canine left ventricular tissues perfused arterially with Tyrode's solution having normal or low potassium concentrations, [K(+)](o). We mapped action potentials (APs) on the cut-exposed transmural surface of the wedges in control, after CsCl, and CsCl with 0.15 mumol/l isoproterenol (CsCl+ISP). CsCl delayed late phase 3 repolarization and prolonged the duration of the AP, more so during low [K(+)](o) perfusion. Rapid pacing induced delayed afterdepolarizations (DADs) in all low [K(+)](o) and in 71% of normal [K(+)](o) preparations after CsCl treatment. Addition of ISP induced DADs in all preparations. DADs originated in mid-to-endocardium, and initiated VT after CsCl+ISP. Migration of DAD-VT foci resulted in multifocal VT. Alternating DADs at 2 foci resulted in bidirectional VT. There were more foci and longer durations of VT at low [K(+)](o) than at normal [K(+)](o). Delayed late phase 3 repolarization of APs and DADs generated U waves. Verapamil abolished all DADs and VT. CsCl blockade of I(K1) produced a ventricular wedge model of ATS. Suppressing I(K1) generated U waves by delaying late repolarization of APs and creating DADs, and promoted polymorphic VT by triggering DADs at multiple shifting sites.

Ventricular ectopy during REM sleep: implications for nocturnal sudden cardiac death

A young adult female presented with syncope and periodic weakness. A 12-lead electrocardiogram showed frequent premature ventricular contractions and prolonged QU interval. Repetitive runs of nonsustained ventricular tachycardia were recorded at night. Electromyography, muscle biopsy, MRI, echocardiography, exercise stress testing using Bruce protocol with microvolt T-wave alternans testing, 24 h Holter monitoring, electrophysiological testing and examination of the effects of sleep and sleep stage on the patient's ventricular arrhythmias. Type 1 Andersen-Tawil syndrome, (also known as type 7 long QT syndrome). Severe ventricular arrhythmia was observed, predominantly during rapid eye movement sleep. We speculate that the autonomic instability present during rapid eye movement sleep precipitates increasing vulnerability to sleep-related ventricular tachycardia. Beta-blocker therapy alone, subsequently combined with mexiletine treatment.

Management and Treatment of Andersen-Tawil Syndrome (ATS)

Andersen-Tawil syndrome (ATS) is characterized by periodic paralysis, cardiac arrhythmias, and distinct facial and skeletal features. The majority of patients with ATS (ATS1) have point mutations in the KCNJ2 gene, which encodes the inward-rectifying potassium channel known as Kir2.1. The skeletal muscle and cardiac symptoms are accounted for, in most cases, by a dominant negative effect of the mutations on potassium channel current, resulting in prolonged depolarization of the action potential. Mechanisms of disruption of channel function include abnormal trafficking and assembly of second messengers such as phosphatidylinositol 4,5-bisphosphate, abnormal gating of the channel, and incorrect folding of the Kir2.1 protein. Less apparent is the mechanism by which these mutations account for the typical facial and skeletal abnormalities. The concomitant involvement of cardiac and skeletal muscle in ATS poses unique treatment and management challenges. Because of differences in cardiac and skeletal muscle physiology, drugs that may have a beneficial effect on cardiac function may have a detrimental effect on skeletal muscle and vice versa. We review the clinical, laboratory, and genetic features of this disorder with particular emphasis on treatment and management.

Genotype-Phenotype Correlation and Therapeutic Rationale in Hyperkalemic Periodic Paralysis

Familial hyperkalemic periodic paralysis (PP) is a dominantly inherited muscle disease characterized by attacks of flaccid weakness and intermittent myotonia. Some patients experience muscle stiffness that is aggravated by cold and exercise, bordering on the diagnosis of paramyotonia congenita. Hyperkalemic PP and paramyotonia congenita are allelic diseases caused by gain-of-function mutations of the skeletal muscle sodium channel, Nav1.4, which is essential for the generation of skeletal muscle action potentials. In this review, the functional and clinical consequences of the mutations and therapeutic strategies are reported and the differential diagnoses discussed. Also, the question is addressed of whether hyperkalemic PP is truly a different entity than normokalemic PP. Additionally, the differential diagnosis of Andersen-Tawil syndrome in which hyperkalemic PP attacks may occur will be briefly introduced. Last, because hyperkalemic PP has been described to be associated with an R83H mutation of a MiRP2 potassium channel subunit, evidence refuting disease-causality in this case will be discussed.

Corticosteroid-exacerbated symptoms in an Andersen's syndrome kindred

Periodic paralysis, cardiac arrhythmia and bone features are the hallmark of Andersen's syndrome (AS), a rare disorder caused by mutations in the KCNJ2 gene that encodes for the inward rectifier K(+)-channel Kir2.1. Rest following strenuous physical activity, carbohydrate ingestion, emotional stress and exposure to cold are the precipitating triggers. Most of the mutations act in a dominant-negative fashion, either through a trafficking dysfunction or through Kir2.1-phosphatidyl inositol bisphosphate binding defect. We have identified two families that were diagnosed with periodic paralysis and cardiac abnormalities, but only discrete development features. The proband in one of the two families reported having his symptoms occurring twice within the day following corticosteroids ingestion, and alleviated after stopping the corticosteroid treatment. Electromyographic evaluations pointed out to a typical hypokalemic periodic paralysis pattern. Molecular screening of the KCNJ2 gene identified two mutations leading to C54F and T305P substitutions in the Kir2.1 protein. Functional expression in mammalian cells revealed a loss-of-function of the mutated channels and a dominant-negative effect when both mutants and wild-type channels are present in the same cell. However, channel trafficking and assembly are not affected. Substitutions at these residues may interfere with phosphatidyl inositol bisphosphate binding to Kir2.1 channels. Sensitivity of our patients to multiple corticosteroid administrations shows that care must be taken in the use of such treatments in AS patients. Taken together, our data suggest the inclusion of the KCNJ2 gene in the molecular screening of patients with periodic paralysis, even when the classical AS dysmorphic features are not present.

Sudden cardiac death in Andersen–Tawil syndrome

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.

An Andersen-Tawil Syndrome Mutation in Kir2.1 (V302M) Alters the G-loop Cytoplasmic K+ Conduction Pathway

Loss-of-function mutations in the inward rectifier potassium channel, Kir2.1, cause Andersen-Tawil syndrome (ATS-1), an inherited disorder of periodic paralysis and ventricular arrhythmias. Here, we explore the mechanism by which a specific ATS-1 mutation (V302M) alters channel function. Val-302 is located in the G-loop, a structure that is believed to form a flexible barrier for potassium permeation at the apex of the cytoplasmic pore. Consistent with a role in stabilizing the G-loop in an open conformation, we found the V302M mutation specifically renders the channel unable to conduct potassium without altering subunit assembly or attenuating cell surface expression. As predicted by the position of the Val-302 side chain in the crystal structure, amino acid substitution analysis revealed that channel activity and phosphatidylinositol 4,5-bisphosphate (PIP2) sensitivity are profoundly sensitive to alterations in the size, shape, and hydrophobicity of side chains at the Val-302 position. The observations establish that the Val-302 side chain is a critical determinant of potassium conduction through the G-loop. Based on our functional studies and the cytoplasmic domain crystal structure, we suggest that Val-302 may influence PIP2 gating indirectly by translating PIP2 binding to conformational changes in the G-loop pore.

Mutations of KCNJ2 gene associated with Andersen–Tawil syndrome in Korean families

Mutations of the KCNJ2 gene are a major underlying cause of Andersen-Tawil syndrome (ATS), a rare autosomal dominant inherited disorder that is characterized by periodic paralysis, cardiac arrhythmias, and developmental dysmorphic features. The KCNJ2 gene encodes an inward rectifying K(+) channel protein, Kir2.1, which plays an important role in maintaining the homeostasis of channel current in various cell types. We have identified two missense mutations of KCNJ2 (R218Q and M307I) in two Korean families diagnosed with ATS. The M307I mutation is a novel mutation, located at the intracellular C-terminal domain, which is known to be concerned with putative phosphatidylinositol 4,5-bisphosphate (PIP(2)) binding and channel trafficking.

Genotype-phenotype correlations ofKCNJ2 mutations in Japanese patients with Andersen-Tawil syndrome

Andersen-Tawil syndrome (ATS) is a rare inherited disorder characterized by periodic paralysis, mild dysmorphic features, and QT or QU prolongation with ventricular arrhythmias in electrocardiograms (ECGs). Mutations of KCNJ2, encoding the human inward rectifying potassium channel Kir 2.1, have been identified in patients with ATS. We aimed to clarify the genotype-phenotype correlations in ATS patients. We screened 23 clinically diagnosed ATS patients from 13 unrelated Japanese families. Ten different forms of KCNJ2 mutations were identified in the 23 ATS patients included in this study. Their ECGs showed normal QTc intervals and abnormal U waves with QUc prolongation and a variety of ventricular arrhythmias. Especially, bidirectional ventricular tachycardia (VT) was observed in 13 of 23 patients (57%). Periodic paralysis was seen in 13 of 23 carriers (57%), dysmorphic features in 17 (74%), and seizures during infancy in 4 (17%). Functional assays for the two novel KCNJ2 mutations (c. 200G>A (p. R67Q) and c. 436G>A (p. G146S)) displayed no functional inward rectifying currents in a heterologous expression system and showed strong dominant negative effects when co-expressed with wild-type KCNJ2 channels (91% and 84% reduction at -50 mV respectively compared to wild-type alone). Immunocytochemistry and confocal imaging revealed normal trafficking for mutant channels. In our study, all of the clinically diagnosed ATS patients had KCNJ2 mutations and showed a high penetrance with regard to the typical cardiac phenotypes: predominant U wave and ventricular arrhythmias, typically bidirectional VT.

Flecainide for recurrent malignant ventricular arrhythmias in two siblings with Andersen-Tawil syndrome

Andersen-Tawil syndrome consists of the clinical triad of potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features.1 The molecular basis of this clinically heterogenic syndrome is linked to mutations in the KCNJ2 gene, which encodes the α-subunit of Kir2.1, an inwardly rectifying potassium channel.2–5 In Andersen-Tawil syndrome or long QT syndrome type 7 (LQTS7), ventricular arrhythmias range from isolated premature ventricular beats to polymorphic ventricular tachycardias (VTs) such as bidirectional VT and, less frequently, torsades de pointes (TdP).