Andersen-Tawil Syndrome Research Articles

Andersen–Tawil syndrome. A diagnostic challenge

Article history: Received 14 November 2015 Accepted 22 November 2015 Available online 26 November 2015 heart sounds by premature beats with compensatory pause. Holter monitoring reported corrected QT interval of 515 ms, and very frequent VPB (32,231/24 h), with multiple morphologies, couplets, bigeminy, and trigeminy. Cardiac Magnetic Resonance reported no structural heart disease. Genetic study was requested using massive sequencing sponsored

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

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

Report of a Turkish girl with Andersen-Tawil syndrome

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.

P162 – 2473: Andersen-Tawil syndrome with myopathy: Case report

Introduction Andersen-Tawil syndrome (ATS) is a rare autosomal dominant potassium channelopathy characterized by periodic paralysis, ventricular arrhythmias, and dysmorphic features. We present a 14-year-old boy with characteristic features of ATS, and childhood onset myopathy. Case report Fourteen years old boy admitted to our clinic with progressive muscle weakness and also described periods of severe weakness attacks for the last two years. Birth and family history were normal except 37 weeks of prematurity. At the age of four he started to fall down while walking and he descibed tiredness. At the age of 6 cardiac arrhythmia was detected. Investigations for muscle weakness showed that serum creatine kinase level was 625 U/L. Electromyography showed myopathic changes. The muscle biopsy didn't demonstrate any specific finding. On his examination there was orbital hypertelorism, micrognathia, low set ears, clinodactyly, short stature, proximal muscle weakness of both upper and lower extremities. Deep tendon reflexes were hypoactive, Gowers sign was positive. On his electrocardiogram ventricular extrasystoles and U waves were seen. With the findings of severe worsening of limb weakness and dysmorphic features with cardiac arrhythmia ATS was suspected. Genetic testing confirmed a heterozygous mutation (R218W) in KCNJ2. After acetazolamide treatment attacks of severe muscle weakness and Gowers sign disappeared. Conclusion Although ATS is charactized with episodes of muscle weakness, fixed myophaty had been reported only in two patients previously. All these two patients and our patient had heterozygous mutation (R218W) in KCNJ2. Because of the life threatening cardiac arrhythmias ATS must also be kept in mind in patients with fixed myophaty.

ANDERSEN-TAWIL SYNDROME: A NOVEL APPROACH FOR THE MANAGEMENT OF VENTRICULAR ARRHYTHMIAS

Andersen-Tawil syndrome (ATS) is a rare autosomal dominant or sporadic disorder defined by a triad of periodic muscle paralysis, ventricular arrhythmias (long QT-7) and dysmorphic features. The underlying mutation is in the KCNJ2 gene encoding the inward rectifier potassium channels (Kir2.1) present

Ion channelopathies in human induced pluripotent stem cell derived cardiomyocytes: a dynamic clamp study with virtual IK1.

Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are widely used in studying basic mechanisms of cardiac arrhythmias that are caused by ion channelopathies. Unfortunately, the action potential profile of hiPSC-CMs—and consequently the profile of individual membrane currents active during that action potential—differs substantially from that of native human cardiomyocytes, largely due to almost negligible expression of the inward rectifier potassium current (IK1). In the present study, we attempted to “normalize” the action potential profile of our hiPSC-CMs by inserting a voltage dependent in silico IK1 into our hiPSC-CMs, using the dynamic clamp configuration of the patch clamp technique. Recordings were made from single hiPSC-CMs, using the perforated patch clamp technique at physiological temperature. We assessed three different models of IK1, with different degrees of inward rectification, and systematically varied the magnitude of the inserted IK1. Also, we modified the inserted IK1 in order to assess the effects of loss- and gain-of-function mutations in the KCNJ2 gene, which encodes the Kir2.1 protein that is primarily responsible for the IK1 channel in human ventricle. For our experiments, we selected spontaneously beating hiPSC-CMs, with negligible IK1 as demonstrated in separate voltage clamp experiments, which were paced at 1 Hz. Upon addition of in silico IK1 with a peak outward density of 4–6 pA/pF, these hiPSC-CMs showed a ventricular-like action potential morphology with a stable resting membrane potential near −80 mV and a maximum upstroke velocity >150 V/s (n = 9). Proarrhythmic action potential changes were observed upon injection of both loss-of-function and gain-of-function IK1, as associated with Andersen–Tawil syndrome type 1 and short QT syndrome type 3, respectively (n = 6). We conclude that injection of in silico IK1 makes the hiPSC-CM a more reliable model for investigating mechanisms underlying cardiac arrhythmias.

Andersen-Tawil syndrome (ATS) – Case report and literature review

Andersen-Tawil Syndrome (ATS) is a rare genetic disorder inherited in an autosomal dominant pattern caused by mutations in the KCNJ2 gene encoding Kir2.1 protein forming potassium ion channel, leading to disruption of cardiac and skeletal muscle repolarisation. Clinical symptoms include periodic paralysis, ventricular arrhythmia associated with QT prolongation and typical skeletal and facial dysmorphic features. The aim of the study was to present characteristic features of the rare Andersen-Tawil syndrome (ATS) within the face and oral cavity of a 9-year-old boy. The patient was diagnosed with Andersen-Tawil syndrome (OMIM#170390) at the age of 8 due to the positive family history, typical dysmorphic features, and the presence of mutation in the KCNJ2 gene confirmed by genetic testing. Typical manifestations of ATS were diagnosed: cardiac arrhythmia, short stature, scoliosis and clinodactyly. Clinical examination revealed typical facial dysmorphic features of ATS: broad forehead, triangular shape of the face, hypertelorism, microstomia, low-set ears, and mandibular retrognathism. Intraoral examination revealed: high-arched palate, crowding in the dental arches, hypomineralisation of enamel and high incidence of dental caries. Dental age assessment by Demirijan pointed to delayed development of permanent dentition. Cephalometric analysis revealed skeletal class II with high angle vertical jaws relation. Diagnosis of ATS requires high index of suspicion because of a great variability in the clinical manifestation of the syndrome. The subtle nature of the dysmorphic features often delays the diagnosis of this syndrome, and its potentially lethal cardiac arrhythmia remaining undetected.

Andersen-Tawil syndrome (ATS) – Case report and literature review

1. Klein R, Ganelin R, Marks JF, Usher P, Richards C. Periodic paralysis with cardiac arrhythmia. J Pediatr. 1963; 62: 371–385. CrossRef Google Scholar

A case of Andersen syndrome with appropriate ICD shock

A case of Andersen syndrome with appropriate ICD shock

Abnormal electroencephalogram, epileptic seizures, structural congenital heart disease and aborted sudden cardiac death in Andersen–Tawil syndrome

Abnormal electroencephalogram, epileptic seizures, structural congenital heart disease and aborted sudden cardiac death in Andersen–Tawil syndrome

Abstract 12704: The Prognosis of Andersen-Tawil Syndrome is Not So Benign as Ever Thought

Rationale: Andersen-Tawil syndrome (ATS) represents ventricular arrhythmia with abnormal U wave, periodic paralysis, and dysmorphysm, resulting from reduction of I K1 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 ventricular arrhythmias, 10 patients (43%) showed periodic pararysis. We compared 23 probands dividing into two groups; one with syncope (n=4), another without syncope (n=19). There are no significant difference in gender, patient number of ventricular arrhythmia, periodic pararysis, and position of KCNJ2 mutations. ECG findings such as HR (61bpm vs. 80 bpm), QTc (439 msec vs. 404 msec), QUc (668 msec vs. 650 msec), and Tpeak-Upeak interval (233 msec vs. 198 msec) showed no significant difference. The age of diagnosis was significantly higher in syncope group (32 ± 9 year old vs. 16 ± 10 year old, P=0.014). Aborted cardiac arrest (n=2, 50% vs. n=0, P=0.0046), beta blocker use (n=4, 100% vs. n=7, 37%, P=0.011) and ICD implantation (n=2, 50% vs. n=0, P=0.0046) were significantly higher in syncope group. Conclusion: We need to watch attentively KCNJ2 positive probands even after childhood.

Andersen-Tawil syndrome: report of 3 novel mutations and high risk of symptomatic cardiac involvement.

Andersen-Tawil syndrome (ATS) is a potassium channelopathy affecting cardiac and skeletal muscle. Periodic paralysis is a presenting symptom in some patients, whereas, in others, symptomatic arrhythmias or prolongation of QT in echocardiographic recordings will lead to diagnosis of ATS. Striking intrafamilial variability of expression of KCNJ2 mutations and rarity of the syndrome may lead to misdiagnosis. We report 15 patients from 8 Polish families with ATS, including 3 with novel KCNJ2 mutations. All patients had dysmorphic features; periodic paralysis affected males more frequently than females (80% vs. 20%), and most attacks were normokalemic. Two patients (with T75M and T309I mutations) had aborted sudden cardiac death. An implantable cardioverter-defibrillator was utilized in 40% of cases. KCNJ2 mutations cause a variable phenotype, with dysmorphic features seen in all patients studied, a high penetrance of periodic paralysis in males and ventricular arrhythmia with a risk of sudden cardiac death.

Muscle channelopathies: recent advances in genetics, pathophysiology and therapy.

This article reviews recent advances in clinical, genetic, diagnostic and pathophysiological aspects of the skeletal muscle channelopathies. Genetic advances include the use of the minigene assay to confirm pathogenicity of splice site mutations of CLC-1 chloride channels and a new gene association for Andersen-Tawil syndrome. Mutations causing a gating pore current have been established as a pathomechanism for hypokalaemic periodic paralysis. Mutations in nonchannel genes, including the mitochondrial mATP6/8 genes, have been linked to channelopathy-like episodic weakness. Advances in diagnostic tools include the use of MRI and muscle velocity recovery cycles to evaluate myotonia congenita patients. Specific neonatal presentations of sodium channel myotonia are now well documented. An international multicentre placebo-controlled randomized clinical trial established that mexiletine is an effective therapy in the nondystrophic myotonias. This is the first evidence-based treatment for a skeletal muscle channelopathy. Recent evidence in mouse models indicated that bumetanide can prevent attacks of hypokalaemic periodic paralysis, but this has not yet been tested in patient trials. Advances in genetic, clinical, diagnostic and pathomechanistic understanding of skeletal muscle channelopathies are being translated into improved therapies. Mexiletine is the first evidence-based treatment for nondystrophic myotonias. Bumetanide is effective in preventing attacks in mouse models of hypokalaemic periodic paralysis and now needs to be tested in patients.

Andersen-Tawil syndrome: a review of its clinical and genetic diagnosis with emphasis on cardiac manifestations

The Andersen-Tawil syndrome is a cardiac ion channel disease that is inherited in an autosomal dominant way and is classified as type 7 of the congenital long QT syndromes. Affected gene is KCNJ2, which forms the inward rectifier potassium channel designated Kir2.1. This protein is involved in stabilizing the resting membrane potential and controls the duration of the action potential in skeletal muscle and heart. It also participates in the terminal repolarization phase of the action potential in ventricular myocytes and is a major component responsible for the correction in the potassium current during phase 3 of the action potential repolarization. Kir 2.1 channel has a predominant role in skeletal muscle, heart and brain. Alterations in this channel produce flaccid paralysis, arrhythmias, impaired skeletal development primarily in extremities and facial area. In this review we address the disease from the point of view of clinical and molecular diagnosis with emphasis on cardiac manifestations.

CARDIAC FEATURES IN ADULTS WITH ALTERNATING HEMIPLEGIA

<h3>Introduction</h3> Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder caused by de novo mutations in the ATP1A3 gene encoding the α3-subunit of the Na+/K+-ATPase transporter, expressed in cardiac and neuronal tissue. AHC is characterised by recurrent plegic attacks, dystonic posturing and seizures. Non-paroxysmal neurological manifestations and developmental delay may occur. Potentially fatal arrhythmias are associated with cardiac channelopathies but also with neurological channelopathies such as Andersen-Tawil syndrome, and postulated in sudden unexplained death in epilepsy. Autonomic dysfunction and one case of asystole have been reported in AHC, but specific cardiac abnormalities have not been defined. <h3>Methods and results</h3> Nine patients from an original UK cohort of twenty-six (adults n=6; children n=3), underwent detailed cardiac and neurological phenotyping, baseline ECG testing and ATP1A3 molecular genetic analysis. Repolarisation abnormalities and varying degrees of intraventricular conduction delay were seen in all six, ATP1A3-mutation bearing, adults. No abnormalities were detected in children. <h3>Conclusions</h3> These cardiac features raise the possibility of an arrhythmogenic potential of a neuronal channelopathy co-expressed in the heart and brain, warranting cardiac surveillance from adolescence into adulthood and further risk prediction strategies in AHC.

The inward rectifier potassium channel Kir2.1 is required for osteoblastogenesis.

Andersen's syndrome (AS) is a rare and dominantly inherited pathology, linked to the inwardly rectifying potassium channel Kir2.1. AS patients exhibit a triad of symptoms that include periodic paralysis, cardiac dysrhythmia and bone malformations. Some progress has been made in understanding the contribution of the Kir2.1 channel to skeletal and cardiac muscle dysfunctions, but its role in bone morphogenesis remains unclear. We isolated myoblast precursors from muscle biopsies of healthy individuals and typical AS patients with dysmorphic features. Myoblast cultures underwent osteogenic differentiation that led to extracellular matrix mineralization. Osteoblastogenesis was monitored through the activity of alkaline phosphatase, and through the hydroxyapatite formation using Alizarin Red and Von Kossa staining techniques. Patch-clamp recordings revealed the presence of an inwardly rectifying current in healthy cells that was absent in AS osteoblasts, showing the dominant-negative effect of the Kir2.1 mutant allele in osteoblasts. We also found that while control cells actively synthesize hydroxyapatite, AS osteoblasts are unable to efficiently form any extracellular matrix. To further demonstrate the role of the Kir2.1 channels during the osteogenesis, we inhibited Kir2.1 channel activity in healthy patient cells by applying extracellular Ba(2+) or using adenoviruses carrying mutant Kir2.1 channels. In both cases, cells were no longer able to produce extracellular matrixes. Moreover, osteogenic activity of AS osteoblasts was restored by rescue experiments, via wild-type Kir2.1 channel overexpression. These observations provide a proof that normal Kir2.1 channel function is essential during osteoblastogenesis.

Ion channel diseases in children

Ion channel diseases are responsible for the occurrence of supraventricular bradycardia and tachycardia, ventricular tachycardia, syncope and sudden death. In the present paper the specific considerations for diagnostic pathways and therapeutic decision making will be focused on for the largest clinical entities, such as the long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia and Andersen-Tawil syndrome. All diseases are characterized by a specific pathognomic electrocardiographic (ECG) alteration. For most of the diseases a variety of mutations have been identified that code for different ion channel proteins. All have a high potential of arrhythmogenicity in common. It is important to know that the ECG alterations are often only transient, which makes repetitive recordings and sometimes provocation maneuvers necessary. The time of onset of disease varies so that the initiation of diagnostics starts at different ages. Therapy often remains an individual choice and is influenced by a number of factors, such as a family history of sudden death.

Erratum: Severe exacerbation of Andersen–Tawil syndrome secondary to thyrotoxicosis

Correction to: Journal of Human Genetics advance online publication, 22 May 2014; doi:10.1038/jhg.2014.43 Since the advance online publication of this article, the authors of the above paper have noticed an error in the list of authors. Article with correct author names now appears in this issue. The online html and pdf versions have also been rectified.

Electrocardiogram in Andersen-Tawil syndrome. New electrocardiographic criteria for diagnosis of type-1 Andersen-Tawil syndrome.

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 tachycardia (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 pathologic U wave. In this article, we aim to provide five new electrocardiographic clues for the diagnosis of ATS1.

Andersen-Tawil syndrome (LQT7) is associated with alterations in left ventricular rotational mechanics

E-mail: nemes.attila@med.u-szeged.hu The goal: Andersen-Tawil syndrome (ATS), also called Andersen Syndrome and Long QT Syndrome 7 (LQT7) is a rare condition. ATS is characterized by episodic flaccid muscle weakness, distinctive dysmorphic features, ventricular arrhythmias and prolonged QT interval in the presence of normal conventional left ventricular (LV) structural and functional parameters. In the normal heart, the LV base rotates clockwise, while the apex rotates counterclockwise during systole, producing a towel-wringing motion of the heart. The difference between the LV base and LV apex is called net twist angle. The present study was designed to assess LV rotational mechanics in ATS by three-dimensional speckle-tracking echocardiography (3DSTE). Patients and Methods: The study comprised 6 patients with ATS, their results were compared to 20 healthy volunteers. Complete two-dimensional Doppler echocardiography and 3DSTE were performed in all cases. 3DSTE was used to measure apical and basal LV rotations and LV twist. Results: During 3DSTE, apical LV rotation proved to be 8.43 ± 1.54 degree, while basal LV rotation was -2.31 ± 1.31 degree, therefore LV twist was 11.12 ± 5.32 degree in healthy subjects. In 3 out of 6 ATS patients, LV basal and LV apical rotation were in the same direction resulting in the near absence of LV twist showing „rigid body rotation”. In the remaining 3 ATS patients, LV apical rotation (2.06 ± 1.30 degree, p <0.05) together with LV twist (6.51 ± 1.28 degree, p <0.05) were significantly decreased as compared to controls. Mean basal rotation showed no significant difference compared to the values of controls (-4.45 ± 1.87 degree, p =NS). Conclusions: Significant alterations in LV rotational mechanics could be demonstrated in ATS by 3DSTE.