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Andersen–Tawil Syndrome

A Comprehensive Review

Pérez-Riera, Andrés Ricardo MD, PhD*; Barbosa-Barros, Raimundo MD; Samesina, Nelson MD, PhD; Pastore, Carlos Alberto MD, PhD; Scanavacca, Mauricio MD, PhD; Daminello-Raimundo, Rodrigo PhD*; de Abreu, Luiz Carlos PhD*,§; Nikus, Kjell MD, PhD¶,‖; Brugada, Pedro MD, PhD#

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doi: 10.1097/CRD.0000000000000326
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Abstract

Andersen–Tawil syndrome (ATS) is a very rare genetic disease with autosomal dominant (AD) transmission caused by loss-of-function mutations in the KCNJ2 gene (chromosome locus 17q24.3) denominated as ATS type 1 (ATS1). This is the gene that encodes the inward rectifier K+ channel (IK1) Kir2.1. KCNJ2 has 2 exons spanning 5.4 kb, with 427 amino acid residues and 48-kD molecular weight. Kir2.1 is expressed in the skeletal muscle, heart, and brain. It is involved in the setting and stabilizing of the resting membrane potential in skeletal and cardiac muscle and has a major role in the terminal portion of the action potential (AP) repolarization at the end of phases 3 and 4 coincident with the descending limb of the T wave and U wave of the 12-lead surface electrocardiogram (ECG).1,2

Kim and Chung3 reported a de novo mutation in the KCNJ2 gene in a patient with ATS. This mutation predicts the substitution of alanine for glycine at position 146 (Gly146Ala, c.437G > C) of Kir2.1 and is located at the extracellular pore loop region that serves as a principal ion-selective filter. The patient did not respond to acetazolamide but experienced an improvement of the paralytic symptoms on treatment with a combination of spironolactone, amiloride, and potassium supplements. The majority of pathogenic variants in KCNJ2 are missense, rarely in-frame deletions4 and a duplication. The p.Arg218Trp pathogenic variant is considered a potential mutational hot spot.5 Large deletions of KCNJ2 with unknown prevalence were reported by Lestner et al6 and Vergult et al7 in 2012 and Marquis-Nicholson et al8 in 2014.

A mutation in the KCNJ5 gene on the chromosome locus 11q24.3 is also responsible for ATS that encodes the G protein-activated inward rectifier K+ channel 4 (Kir3.4). In 2014, Kokunai et al9 identified a patient with periodic paralysis, episodic flaccid weakness, a characteristic TU wave pattern, ventricular arrhythmias (VAs), and dysmorphic features without primary aldosteronism, who had a p.Gly387Thr variant in KCNJ5 causing ATS by an inhibitory effect on Kir2.1. The authors proposed that KCNJ5 is a second gene causing ATS (ATS2). The inhibitory effects of mutant Kir3.4 on inwardly rectifying K+ channels may account for the clinical presentation in both skeletal and heart muscles.9 ATS2 can also be sporadic/de novo without mutation.

Clinically, ATS is characterized by a triad of muscle weakness (K+-sensitive periodic paralysis), VAs, and dysmorphic features. Some affected individuals have short stature and scoliosis. Other dysmorphic features include as follows:

Facial: Low-set ears, hypertelorism, short palpebral fissures, broad forehead, triangular face, mild facial asymmetry, maxillary and mandibular hypoplasia, broad root of the nose, micrognathia, arched palate, persistent primary dentition, oligodontia, and crowded teeth;

Cranial: Scaphocephalic skull: elongated, keel-like shape (Fig. 1A).

FIGURE 1.
FIGURE 1.:
Andersen-Tawil syndrome phenotypes. A, Scaphocephaly. B, Clinodactyly. C, Brachydactyly. D, Syndactyly.

Limbs: Fusion of the second and third toes (clinodactyly) or “ring finger” (curvature of a finger or toe in the plane of the palm, most commonly the fifth finger towards the adjacent fourth finger), brachydactyly and mild syndactyly, small hands and feet (<10 percentile for age), and joint laxity (Fig. 1B–D).

Affected individuals present in the 1st or 2nd decade with either cardiac symptoms (palpitations and/or syncope) or weakness that occurs spontaneously following prolonged rest or rest after exertion. Mild permanent weakness is common. Mild learning difficulties and a distinct neurocognitive phenotype (ie, deficits in executive function and abstract reasoning) have also been described.

Krych et al10 in 2017 compared clinical presentations in carriers versus noncarriers (n = 25 vs n = 19) of KCNJ2 mutations, including polymorphism in K897T and H558R. Micrognathia and clinodactyly of fingers were more frequent in the carriers: 60% versus 26% and 36% versus 5%, respectively.

BRIEF HISTORY

The first description of periodic paralysis with cardiac arrhythmias was probably made by Klein et al11 in 1963. However, dysmorphisms were not mentioned in any of the cases described by these authors.12 ATS was named after Andersen et al who described the triad of symptoms in 1971,13,14 and Tawil et al15 who made significant contributions to the understanding of the condition in 1994.

NOMENCLATURE OBSERVATIONS/CRITICISMS/OTHER NAMES

Andersen cardiodysrhythmic periodic paralysis, long QT syndrome (LQTS) 7, K+-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features are some nomenclatures attributed to ATS. In 2018, it was postulated that ATS should not be classified as a LQTS because of the lack of QT/QTc prolongation (only the QU interval is typically prolonged).16 QT interval prolongation increases the risk of cardiac events in patients with LQTS, but QU-prolongation does not have a strong prognostic significance in patients with ATS. The occurrence of sudden cardiac death is relatively infrequent when compared with other LQTS.17 Additionally, 36% of patients, who underwent genetic testing for catecholaminergic polymorphic ventricular tachycardia (CPVT), had a gene mutation of ATS1 or LQTS.18 Some patients with a KCNJ2 gene mutation have been designated as CPVT3, mainly due to clinical similarities between the 2 syndromes.19,20 Although listed in Online Mendelian Inheritance in Man (OMIM), some older names for the ATS (periodic paralysis, potassium-sensitive cardiodysrhythmic type, and Andersen cardiodysrhythmic periodic paralysis) are no longer in clinical use.

GENETIC ASPECTS

ATS is a genetic disorder, which, in the majority of cases, is caused by variants in the KCNJ2 gene, or more rarely in the KCNJ5 gene. One mutated copy of the gene in each cell is sufficient for a person to be affected by an AD disorder. This means that an individual with a pathogenic variant has a 50% chance of passing it to their offspring. The condition could also result from a new mutation in the gene in a person with no history of the disorder in their family.12

Two ATS types have been described, distinguished by the genetic abnormality:

ATS1, OMIM 170390, accounts for about 50–60% of cases1,21 of this syndrome and is caused by 1 or more of 16 mutations in the KCNJ2 gene (potassium voltage-gated channel subfamily J member 2 gene).22 This gene has been mapped to chromosome 17q23 and encodes the inward rectifier K+-channel Kir2.

Another variant causes mutation in the KCNJ5 gene, which codes a 419-amino-acid G protein-activated inwardly rectifying potassium channel protein 4 (Kir3.4). KCNJ5 is expressed in cardiac and skeletal muscle23 and encodes an integral membrane protein, which belongs to 1 of 7 subfamilies of inward-rectifier potassium channel proteins called potassium channel subfamily J. The encoded homotetrameric protein is a subunit of the K+ channel. It is controlled by G-proteins and has a greater tendency to allow K+ to flow into a cell rather than out of a cell. Naturally, occurring mutations in this gene are associated with aldosterone-producing adenomas.

ATS2, OMIM 600734, locus 11q24.3, which is the long (q) arm of chromosome 11 at position 24.3, KCNJ5 or K+ voltage-gated channel subfamily J member 5, accounts for about 15% of cases. Also known as GIRK4, a potassium channel controlled by G proteins, encodes protein-sensitive inwardly rectifying K+ channels (Kir3.4) which carry the acetylcholine-induced potassium current.24 Variants in a related gene encoding a similar potassium ion channel, KCNJ5 has been identified in some individuals with ATS2, but in many cases, no genetic variant was found. The KCNJ5 gene provides instructions for making a protein that functions as a potassium channel, which means that it transports positively charged atoms (ions) of K+ into and out of cells. K+ channels produced from the KCNJ5 gene are found in several tissues, including the adrenal glands. In these glands, the flow of ions creates an electrical charge across the cell membrane, which affects the triggering of certain biochemical processes that regulate aldosterone production. Aldosterone helps to control blood pressure by maintaining proper salt and fluid levels in the body. The protein made by the KCNJ2 gene forms an ion channel that transports K+ into muscle cells. This specific channel (the inward rectifier potassium channel Kir2.1) carries a K+ current known as IK1 which is responsible for setting the resting membrane potential of muscle cells and is therefore critical for maintaining the normal functions of skeletal and cardiac muscle.12 Pathogenic variants in the KCNJ2 gene alter the usual structure and function of potassium channels or prevent the channels from being inserted correctly into the cell membrane. Many variants prevent a molecule called phosphatidylinositol biphosphate from binding to the channels and effectively regulating their activity. These changes disrupt the flow of potassium ions, leading to the periodic paralysis and abnormal heart rhythms characteristic of ATS.13 Kokunai et al9 described a proband that exhibited episodic flaccid weakness and a characteristic TU wave pattern suggestive of ATS, but that did not harbor KCNJ2 mutations. The authors performed exome capture resequencing by restricting the analysis to genes that encode ion channels/associated proteins. The functional consequences of the mutation were investigated using a heterologous expression system in Xenopus oocytes, focusing on the interaction with the Kir2.1 subunit. They identified a mutation in the KCNJ5 gene. The coexpression of Kir2.1 and mutant Kir3.4 in Xenopus oocytes reduced the inwardly rectifying current significantly compared with that observed in the presence of wild-type Kir3.4. The authors proposed that KCNJ5 is a second gene causing ATS. The inhibitory effects of mutant Kir3.4 on inwardly rectifying potassium channels may account for the clinical presentation in both skeletal and heart muscles.9 Thereby, ATS2 may be caused by a mutation in the KCNJ5 gene, which codes a 419-amino-acid G protein-activated inwardly rectifying potassium channel protein 4 (Kir3.4).

Genetic Allelic Disorders Related to the KCNJ2 Gene

Familial Atrial Fibrillation 9 (OMIM 613980)

Gene: KCNJ2, protein voltage-gated K+ channel, Kv11.1; a rapid delayed rectifier K+ channels (IKr) pathogenic missense variant was described in a Chinese family; 5 affected individuals and 2 individuals who did not have atrial fibrillation were positive for the variant.25

Congenital Short QT Syndrome Type 3 (OMIM 609622)

A KCNJ2 pathogenic missense variant, potassium inwardly rectifying channel, subfamily J, member 2. It was identified in a 5-year-old female and her father who had short QT syndrome (SQT) intervals (QTc duration between 315 and 320 ms) and asymmetric T waves on the ECG. Pathogenic variants in KCNH2 and KCNQ1, the 2 genes associated with SQT syndrome, were not identified. Priori et al26 identified a missense mutation in the KCNJ2 gene (600681.0010). The mutation was not present in the unaffected mother or in the paternal grandparents, indicating that it may have occurred de novo in the father. A novel form of the SQT3 is caused by a mutation in the KCNJ2 gene. The affected members of a single family had a G514A substitution in the KCNJ2 gene that resulted in a change from aspartic acid to asparagine at position 172 (D172N). This is the third variant of the SQT3. These mutations were observed in 2 patients. On routine clinical evaluation, an asymptomatic 5-year-old girl was found to have an abnormal ECG with a markedly SQT interval (315 ms) and narrow-based and peaked T waves. Her 35-year-old father had a SQT interval (320 ms) and a history of near-syncopal episodes and palpitations since adolescence. ECGs of the proband and her father were characterized by asymmetric T waves with a rather normal ascending ramp and a remarkably rapid descending terminal ramp. The mother and the paternal grandparents had unremarkable ECGs and reported no family histories of sudden death. A genetic defect in the KCNJ2 gene caused a significant increase in the outward Ik1 current leading to an acceleration of the final phase of the repolarization. A novel heterozygous gain-of-function KCNJ2 mutation (M301K) in the inward rectifier potassium channel gene was reported in 8-year-old girl with paroxysmal atrial fibrillation, who had an extremely SQT interval.27 Another mutation described is E299V in KCNJ2, the gene that encodes the strong inward rectifier K+ channel protein (Kir2.1).28 Proarrhythmic AP changes were observed with both loss-of-function and gain-of-function IK1 (Kir2.2) ATS1, LQTS 7, and SQTS 3, respectively.29

Genetic Allelic Disorders Related to the KCNJ5 Gene

Type III Familial Hyperaldosteronism and LQTS 13

The syndrome is related to the oxytocin signaling pathway and inwardly rectifying K+ channels.30 Gene ontology annotations related to this gene include inward rectifier K+ channel activity and G-protein activated inward rectifier K+ channel activity. An important paralog of this gene is KCNJ6. Yang et al31 identified KCNJ5, encoding Kir3.4, as a causative gene in LQTS. In a large Chinese family with LQTS, they detected a mutation, Gly387Arg, in a highly conserved residue in Kir3.4. The Kir3.4-Gly387Arg mutation resulted in a loss of IKACh channel function by disrupting membrane targeting and stability of Kir3.4. A mutation in Kir3.4 exerts dominant-negative effects on Kir3.1/Kir3.4 channel complexes, linking it to congenital LQTS. This suggests a potential role for these channels in ventricular repolarization.31

EPIDEMIOLOGY

ATS is a very rare multisystemic channelopathy. Up to the year 2013, approximately 200 cases had been described in the medical literature.12 The condition is estimated to affect 1 person in every 1,000,000,12 with an estimated prevalence of 1 in 500,000. Researchers believe that ATS accounts for less than 10% of all cases of periodic paralysis.

CLINICAL DIAGNOSIS

ATS is generally diagnosed at an early age (1st or 2nd decade) based on symptoms, such as palpitations, syncope, weakness that occurs spontaneously following prolonged rest or rest after exertion, characteristic dysmorphism on physical examination, analysis of the first-degree family members, and the results of ECG and Holter monitoring.12 Diagnostic clinical criteria have been proposed, and based on them, a diagnosis can be made if 2 of the following 4 criteria are met as follows: (1) periodic paralysis; (2) polymorphic ventricular contractions or ventricular tachycardia (VT), a prolonged QU/QUc, and/or a prominent U wave; (3) at least 2 of the following dysmorphic features: low-set ears, wide-set eyes, a small mandible, fifth-digit clinodactyly, syndactyly, and low stature; and (4) a family member with confirmed ATS.12 Ardissone et al32 commented that it can be difficult to appreciate the facial features of individuals in a family photo. However, in all the reports in which the skeletal phenotype is shown, the faces of those affected are so similar that they could pass for members of the same family. This is even more noticeable in ATS patients from nonwhite populations in Mexico.33

Genetic testing can be used to identify the specific variant in an affected person, and this can aid in family screening12 and/or identification of KCNJ2 mutations. The diagnosis of ATS might be suspected in individuals with 2 of the following 3 criteria24: (1) periodic paralysis; (2) symptomatic cardiac arrhythmias or evidence of enlarged U waves, ventricular ectopy, or a prolonged QTc or QUc interval on the ECG; and (3) characteristic facial features, dental abnormalities, small hands and feet, and at least 2 of the following: low-set ears, wide-set eyes, small mandible, fifth-digit clinodactyly, syndactyly, or 1 of the above 3 criteria in addition to at least 1 other family member who meets 2 of the 3 criteria. The presence of a mutation in the KCNJ2 gene confirms the diagnosis of ATS1.24

Other investigations that may be helpful in making a diagnosis include the measurement of blood potassium levels at baseline and during periods of weakness and measurement of thyroid function.34

Conventional Classification for Periodic Paralysis

Primary or Familial Periodic Paralysis

The 2 most common types of periodic paralyzes are hypokalemic periodic paralysis which is characterized by a fall in potassium levels in the blood and hyperkalemic periodic paralysis which is characterized by a rise in potassium levels in the blood. All forms have AD inheritance. However, in ATS, serum K+ concentration during episodes of weakness are most frequently low (<3.5 mmol/U).34,35

Secondary Periodic Paralysis

Etiologic factors include as follows: hypokalemic periodic paralysis, thyrotoxicosis, thiazide- or loop-diuretic induced, potassium-losing nephropathy, drug-induced (gentamicin, carbenicillin, amphotericin B, alcohol), primary or secondary hyperaldosteronism, and gastrointestinal potassium loss.

Electrocardiogram and Arrhythmias

The 12-lead ECG may reveal characteristic abnormalities.17,34,36–38 Prominent U waves that occur paradoxically at faster heart rates (HRs) or epinephrine infusion suggest that this may represent a manifestation of channelopathy rather than a normal variant. In normal conditions, U wave voltage is strongly rate-dependent (inversely proportional). A U wave is more easily observed during bradycardia than during faster HRs. When the HR is less than or equal to 65 beats per minute (bpm), U waves are visible in 90% of individuals. When the HR is between 80 and 95 bpm, U waves are visible in 65% of cases. When the HR is greater than 95 bpm, U waves are visible in 25% of cases.39 Prominent and broad U waves in ATS is a consequence of slowed terminal phase 3 of the AP40 and terminal phase 4, coincident with the U wave of surface ECG (Fig. 2).

FIGURE 2.
FIGURE 2.:
Typical ECG in a patient with ATS1. Clinical features: 23-year-old female, no characteristic phenotype or skeletal muscle disease. Positive KCNJ2 mutation. She suffered from ventricular arrhythmias during pregnancy and puerperium. She underwent cardiac pacemaker implantation (DDD) in June 2019 and has remained asymptomatic since. She has a sister with a confirmed genotype. Her mother had implantable cardioverter-defibrillator implantation at 28 years of age, and a cousin had aborted sudden death. ECG analysis: (A) 12-lead ECG diagnosis: HR 54 bpm, SÂP 69°, PR interval 174 ms, QRS duration 98 ms, QRS axis 75°, and QT/QTc = 366/351 ms. B, Very prolonged QU interval (740 ms), giant U wave voltage: U > T. a: tangent line method was used for measuring the QT interval. ATS1 indicates ATS type 1; bpm, beats per minute; DDD, dual chamber pacemaker; ECG, electrocardiogram; HR, heart rate.

Proposed Mechanism of Prolonged QU Interval and Prominent U Wave Genesis in ATS

In normal conditions, during phase 3 of the AP (the “rapid repolarization” phase), and concomitant with the T wave/T-loop of the surface ECG and vectorcardiography, the L-type Ca2+ channels close, while the slow delayed rectifier (IKs) K+ channels remain open as more K+ channels open. This ensures a net outward positive current, corresponding to a negative change in membrane potential, thus allowing other types of K+ channels to open. These are primarily the rapid delayed rectifier K+ channels (IKr) and the inwardly rectifying K+ current, which are affected in ATS1. A mutation in the Kir2.1 gene affects the protein of the inwardly rectifying K+ current, causing a decrease in the output of K+, thus preventing the cell from completing its repolarization. As a result of this, repolarization at the end of phase 3 (prolonged terminal T wave downslope) and phase 4 is prolonged, expressed in the ECG as a broad TU wave junction (present in 43% of cases).17 In addition, there is a high-voltage, prolonged U wave in 73% of the cases,17 and eventually a biphasic or bimodal U wave shape and very prolonged QU interval (≈600–625 ms) with normal or near-normal QT/QTc intervals. The “U on P” sign may be seen: masquerading of next beat P wave by the U wave—the pseudo “tee-pee sign.” During an extrasystole, there is a prolongation of the descending limb of the T wave + U wave. In ATS1, the QT interval can appear prolonged and difficult to measure because of a prominent U wave. In order to properly determine the QT interval, the tangent technique should be carefully applied. Although “classic” ECG presentations of common electrolyte disturbances are well described, multiple electrolyte disturbances occurring simultaneously may generate ECG abnormalities that are not as readily recognizable. The “tee-pee sign” ECG is a manifestation of the imbalance of multiple electrolytes. Johri et al41 reported a case of hyperkalemia with concurrent hypocalcemia and hypomagnesemia resulting in peaking of the T wave, a prominent U wave, and prolongation of the descending ramp of the T wave, such that it overlapped with the next P wave (“tee-pee” sign), similar to ATS1.

A prominent U wave in the inferior leads is another important feature observed in ATS1. In a recent manuscript from Krych et al10 of ATS patients with polymorphism mutation carriers K897T (ATS1), a U wave was observed in 52% of cases versus 5% in noncarriers.

In normal conditions, the U wave is observed in the precordial leads (semi-direct leads, mainly in V3), but not in the frontal plane. In ATS1, the ECG frequently shows clear U waves in the inferior leads. On the other hand, in normal conditions, the net outward positive current (equal to loss of positive charge from the cell) causes the cell to repolarize. The delayed rectifier K+ channels close when the membrane potential is restored to about –85 to –90 mV, while in IK1, there is conduction throughout phase 4, which helps to set the resting membrane potential.23

The ultimate resting membrane potential due to a not fully activated Kir2.1 IK1 may lead to a small deviation on the ECG. When this deviation becomes bigger, that is, in the presence of a reduced IK1, the U wave becomes bigger, and when the deviation becomes smaller, the U wave becomes smaller in amplitude. Figure 3 shows normal AP (A) and AP in ATS1 (B), with a prominent U wave in the surface ECG.

FIGURE 3.
FIGURE 3.:
Representation of normal action potential/ECG and in ATS. A, Normal monophasic rapid fibers AP/surface ECG correlation: the T wave/T-loop is coincident with phase 3 of the monophasic AP and its end is concomitant with the maximal diastolic potential (MDP) of the AP. MDP is the most negative level attained during the cardiac cycle by the cell membrane of a fiber that does not have a constant resting potential, occurring at the end of phase 3 of the AP. In pacemaker cells, this is the point of hyperpolarization. B, Monophasic rapid fibers AP/surface ECG correlation in ATS. Often the descending ramp of the T wave overlaps with the P wave of the next beat, giving the false impression of being a biphasic U wave. AP indicates action potential; ATS, Andersen–Tawil syndrome; DAD, delayed afterdepolarization; EAD, early afterdepolarization; ECG, electrocardiogram.

Frequent extrasystoles at rest (Fig. 4) with a right bundle branch block (RBBB) pattern, were suppressed at peak exercise, and increased at recovery during exercise treadmill test. In a malignant variant with deletion of the KCNJ2 protein (c.271 282del12 [p.Ala91 Leu94deletion]), exercise testing triggered polymorphic ventricular contractions and bidirectional VT (BVT) similar to CPVT was observed.4

FIGURE 4.
FIGURE 4.:
Twelve-lead ECG showing frequent extrasystoles at rest with the R-on-T phenomenon (superimposition of an ectopic beat on the T wave of a preceding beat) and QRS axis in the frontal plane with left posterior fascicular block-like morphology (extrasystole-QRS axis + 120°) alternating with normal baseline QRS axis. In the precordial leads, nonsustained BVT with RBBB morphology. BVT indicates bidirectional ventricular tachycardia; ECG, electrocardiogram; RBBB, right bundle branch block.

The normal value for the QTc is 350–440 ms or 446 ± 15%. Definitions of a normal QTc vary at levels of ≤400, ≤410, ≤420, or ≤440 ms.42,43 For risk of sudden cardiac death, the “borderline QTc” is 431–450 ms in males and 451–470 ms in females, and “abnormal” QTc is greater than 450 ms in males and greater than 470 ms in females. If the HR is not very high or low, the upper limits of QT can be roughly estimated by taking QT = QTc at a HR of 60 bpm and subtracting 20 ms from QT for every 10-bpm increase in HR. For example, with a HR of 60 bpm, the normal QTc of ≤420 ms is expected. For a HR of 70 bpm, the QT should be ≤400 ms. Likewise, for 80 bpm, the QT should be ≤380 ms. In patients with ATS, Krych et al10 found that the prevalence of QTc greater than 440 ms for males and greater than 460 ms for females was 28% versus 5% in carriers versus noncarriers.

In ATS, a postextrasystole “pseudo-LQTS-pattern” is characteristic: QU interval prolongation with abnormal prominent U wave and increased QTU interval, but no QT interval prolongation. An abnormal TU wave is present in greater than 90% of ATS1 cases.

In ATS, the interval from the apex to the end of T wave (Tpeak–Tend interval or Tpe) is prolonged (>94 ms) as a consequence of a delayed descendent limb of the T wave (near symmetric T wave/TU wave). Tpe may correspond to the transmural dispersion of repolarization, and consequently, the amplification of this interval is associated with malignant VAs.

In patients with ATS, a wide TU wave junction is found in 43%, a prominent U wave from V2 to V4 in greater than 85%, a biphasic U wave in 16%, and a large U wave in 73 % of cases.

During an extrasystole, there is a prolongation of the descending limb of the TU wave. Hyperkalemia with concurrent hypocalcemia and hypomagnesemia resulted in (1) peaking of the T wave, (2) a prominent U wave, and (3) prolongation of the descending limb of the T wave such that it overlapped with the next P wave. In this particular ECG from a patient with combined electrolyte imbalance, we have dubbed the unusual appearance of the segment between the peak of the T wave to the next P wave as the “tee-pee” sign.41

BVT is the hallmark of ATS1 and CPVT. In ATS1, PVT and/or BVT are relatively slow, well-tolerated, and usually asymptomatic with a HR of about 130–140 bpm (Fig. 5).44

FIGURE 5.
FIGURE 5.:
Twelve-lead ECG with BVT with RBBB pattern at rest.44 BVT indicates bidirectional ventricular tachycardia; ECG, electrocardiogram; FC, heart rate (HR); RBBB, right bundle branch block.

Bidirectional Ventricular Tachycardia

BVT is a unique VA characterized by regular (or irregular) VT with complete RBBB or complete left bundle branch block (LBBB) patterns, determining the presence of 2 morphologies of the QRS. In addition, there is typically alternating beat-to-beat spatial QRS axis (SÂQRS) in the frontal plane, with differences of ≈180°: one beat has SÂQRS between –60° and –90°, and the following ≈+120° to +130°. Triggered activity (TA) and reentry are possible mechanisms. Possible causes of BVT are:

Cardiac Channelopathies and Genetic Entities

Familial CPVT, ATS,45 left ventricular noncompaction,46 and hypokalemic periodic paralysis.47

Acquired

Severe digoxin toxicity,48 BVT herbal aconite poisoning,49 pheochromocytoma,50,51 subacute myocarditis,52 myocardial infarction/ischemia,53 and ischemic cardiomyopathy during ablation in the absence of acute coronary syndrome. BVT is observed more frequently in elderly patients. Both severe digoxin intoxication and ATS have BVT as the VA hallmark.

When a patient presents with de novo VT with alternating morphology on the ECG, scar-mediated reentry VT should be considered as a differential diagnosis. Scar-mediated VT may present with VT of various morphologies as a consequence of multiple exit sites54 and may be caused by cardiac metastasis,55 cardiac sarcoidosis,56 dilated cardiomyopathy,57 and hypokalemia.58

Pseudo BVT was observed by Serra et al59 in a patient with transient complete atrioventricular block after dual chamber pacemaker implantation, which was secondary to extrasystoles with retrograde ventriculoatrial conduction and alternating anterograde atrioventricular conduction.

ATS increases the risk of arrhythmias by disturbing the electrical signals that normally coordinate individual heart cells. The genetic variant disturbs an ion channel responsible for the flow of K+, reducing the IK1 current. This prolongs the cardiac AP—the characteristic pattern of voltage changes across the cell membrane that occur with each heartbeat and depolarizes the resting membrane potential of cardiac and skeletal muscle cells.12 When relaxed, these cells have fewer positively charged ions on the inner side of their cell membrane than on the outer side, referred to as being polarized.60 The main ion current responsible for maintaining this polarity is IK1, and a decrease in this current leads to less polarity at rest, or a depolarized resting membrane potential. When these cells contract, positively charged ions, such as sodium and calcium, enter the cell through ion channels, depolarizing or reversing this polarity. After a contraction has taken place, the cell restores its polarity by allowing positively charged ions, such as potassium to leave the cell, restoring the membrane to its relaxed, polarized state.60 The genetic variant found in ATS, leads to a decrease in the flow of potassium, slowing of the rate of repolarization, which can be seen in individual cardiac muscle cells as a longer AP, and on the surface ECG as a prolonged QT interval.12 The underlying mechanisms responsible for the arrhythmias seen in ATS are early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs).

Arrhythmias by Triggered Activity

TA depends on the oscillations of AP that originate potentials that spread during the process of repolarization in phases 2 or 3 (EAD) or when repolarization is completed in phase 4 (DAD) (Fig. 6). TA is defined by impulse initiation caused by afterdepolarizations (membrane potential oscillations that occur during or immediately following a preceding AP).61 Afterdepolarizations occur only in the presence of a previous AP (the trigger), and when they reach the threshold potential, a new AP is generated. This may be the source of a new triggered response, leading to self-sustaining TA.

FIGURE 6.
FIGURE 6.:
Representation of triggered activity. A, Early afterdepolarization in phases 2 and 3. B, Delayed afterdepolarization.

EAD-Induced Triggered Activity

EADs occur when AP duration is prolonged and stop when repolarization is complete, are suppressed by “fast pacing,” and are observed in 2 AP levels (between 0 and –30 mV and between –60 and –70 mV). They have a tendency to occur in runs. Agents and manipulations that may lead to EADs include slow rate (bradycardia, complete heart block), mechanical stretch, hypokalemia, hypoxia, aconitine, hypothermia, low extracellular K+, Ca2+, or magnesium (Mg2+) concentration, class IA antiarrhythmic drugs (quinidine, disopyramide, procainamide), class IB antiarrhythmic drugs (flecainide, encainide, indecainide), class III antiarrhythmic drugs (amiodarone, sotalol, bretylium), phenothiazines, tricyclic and tetracyclic antidepressants, erythromycin, antihistamines, cesium, amiloride, barium, hyperadrenergic state (subarachnoid hemorrhage), mitral valve prolapse, and ethylenediaminetetraacetic acid.

This type of TA is not expected to follow premature stimulation (which is associated with an acceleration of repolarization that decreases the EAD amplitude), with the exception of a long compensatory pause following a premature stimulus, which can be even more important than bradycardia in initiating torsade de pointes.62 Some antiarrhythmic agents, especially class IA and III drugs, may become proarrhythmic because of their therapeutic effect of prolonging the AP. Many drugs can predispose to the formation of EADs, particularly when associated with hypokalemia and/or bradycardia, additional factors that result in prolongation of the AP. Catecholamines may enhance EADs by augmenting the Ca2+ current; however, the resultant increase in HR along with the increase in K+ current effectively reduces the AP duration and thus abolishes EADs.63

EADs are divided into the following:

Phase 2: AP, dome, or “plateau” phase of the AP

In this phase, the AP remains almost constant, as the membrane balance between K+ (moving out of the cell) and Ca2+ (moving into the cell) currents. In this phase, slow inward Ca2+ traffic by the slow ICa-L channel occurs.

Phase 2 AP is a period in which membrane potentials become relatively stable for up to several hundred milliseconds. During this phase, Ca2+ entry, via L-type calcium channels, triggers contraction. Counter-balancing the Ca2+ influx, K+ cations pass through the membrane in the outward direction, resulting in a balance between inward and outward currents.64 This phase is a period of high membrane resistance65 and little current flow. Consequently, small changes in either repolarizing or depolarizing currents can have profound effects on the AP duration and profile. As a wide variety of agents and conditions can result in a decreased outward current or increased inward current (thereby shifting the normal outward current), they can establish the conditions necessary for EAD.

Phase 3 of fast repolarization

These post-depolarizations occur during phase 3 of AP by reduction in the activity of outward K+ channels (Ik-R or Ik-s) as it happens in congenital LQT2 and LQT1, respectively. The latter differentiates from the former in that they present Ca2+ release from the Ca2+ release channel or ryanodine receptor. Both phases may appear during similar experimental conditions, but they differ morphologically as well as in the underlying ionic mechanism.

Phase 2 EADs appear to be related to ICa-L current,66 while phase 3 EADs may be the result of electronic current across repolarization or the result of low IK1.67

DAD-Induced Triggered Activity

A DAD is an oscillation in membrane voltage that occurs after completion of the repolarization of the AP (during phase 4). These oscillations are caused by a variety of conditions that raise the diastolic intracellular Ca2+ concentration, which cause Ca2+ mediated oscillations that can trigger a new AP if they reach the stimulation threshold.68 Digitalis intoxication was the first observed cause of DAD.69 This occurs via inhibition of the Na+/K+ pump, which promotes the release of Ca2+ from the sarcoplasmic reticulum. Clinically, BVT caused by digoxin toxicity is considered an example of TA.70 Catecholamines can cause DADs by causing intracellular Ca2+ overload via an increase in ICa-L and the Na+/Ca2+ exchange current, among other mechanisms. Ischemia-induced DADs are thought to be mediated by the accumulation of lysophosphoglycerides in the ischemic tissue,71 with subsequent elevation in Na+ and Ca2+. Abnormal sarcoplasmic reticulum function (mutations in the ryanodine receptor) can also lead to intracellular Ca2+ overload, facilitating clinical arrhythmias such as CPVT.72 A critical factor for the development of DADs, is the duration of the AP. Longer APs are associated with more Ca2+ overload and facilitate DADs. Therefore, drugs that prolong AP (class IA antiarrhythmic agents) can occasionally increase DAD amplitude. Triggered arrhythmias induced by DADs may be terminated by single stimuli. Therefore, other electrophysiologic features are needed to distinguish them from the reentrant tachycardias. The rate dependency of the coupling interval may be useful, because in most cases of DAD-induced arrhythmias, the shorter the cycle of stimulation, the shorter the coupling interval to the induced arrhythmia. This is in contrast to the inverse relationship seen in reentrant arrhythmias, where the shorter the coupling intervals of the initiating stimuli, the longer the coupling interval of the first arrhythmic beat. Since this is not always the case, other electrophysiologic properties must be taken into account. Adenosine has been used as a test for the diagnosis of DADs. Adenosine reduces the Ca2+ inward current indirectly by inhibiting effects on adenylate cyclase and cyclic adenosine monophosphate. Thus, it may abolish DADs induced by catecholamines but does not alter DADs induced by Na+/K+ pump inhibition. The interruption of VT by adenosine points toward catecholamine-induced DADs as the underlying mechanism.

Clinical examples, where DADs may be involved, are atrial tachycardia, digitalis toxicity-induced tachycardia, accelerated ventricular rhythms in the setting of acute myocardial infarction, some forms of repetitive monomorphic VT, reperfusion-induced arrhythmias, right ventricular outflow tract VT, exercise-induced VT (CPVT), and ATS1.

The main clinical causes and arrhythmias responsible for DAD are ischemia and reperfusion, digitalis intoxication (atrial tachycardia, junctional VT, and BVT), catecholamine-dependent VT, hypercalcemia, multifocal or chaotic atrial tachycardia, multiple foci with triggered automaticity by delayed APs in phase 4, originated by increase of circulating catecholamines, hypoxia, increase of CO2, hypopotassemia, hypomagnesemia, idiopathic VT of the right and left ventricular outflow tract and some idiopathic VTs CPVT, and ATS.

Decreased amplitude of the IK1 causes a repolarizing current at the end of the AP and less current to keep the resting membrane stable. In the experimental isolated canine tissue model, Morita et al40 demonstrated that in ATS, the extrasystoles/VT result from DADs in ventricular myocytes. Also, adrenergic stress increases the ectopic load,36 which fits with TA as the mechanism. Additionally, an increased automaticity as a consequence of decreased IK1 could be the arrhythmogenic substrate,73 and arrhythmias based on this mechanism also increase during epinephrine infusion. An eventual specific role of Purkinje fibers in ATS has not been studied experimentally. A highly vulnerable arrhythmic substrate exists in the specialized conduction system with high local loss of IK1 activity. Ventricular extrasystoles, although highly polymorphic, are characterized by narrow QRS complexes, suggesting a Purkinje fibers origin. Ventricular extrasystoles originating from Purkinje fibers was reported by Smith et al.74 However, radiofrequency catheter ablation is not indicated due to the polymorphic nature.75

The prolonged APs can lead to arrhythmias through several potential mechanisms. The frequent extrasystoles and BVT typical of ATS are initiated by a triggering beat in the form of an afterdepolarization. EADs, occurring before the cell has fully repolarized, arise due to reactivation of calcium and sodium channels that would normally be inactivated until the next heartbeat is due. Under the right conditions, reactivation of these currents can cause further depolarization of the cell, facilitated by the Na+/Ca2+ exchanger.76,77 EADs may occur as single events, but they may also occur repeatedly leading to multiple rapid activations of the cell.76

DADs, occurring after an AP is completed, arise from the spontaneous release of Ca2+ from the sarcoplasmic reticulum. This Ca2+ release then leaves the cell through the Na+/Ca2+ exchanger in exchange for Na+, generating a net inward current and depolarizing the cell membrane.76 If this transient inward current is large enough, a premature AP is triggered. The muscle weakness seen in ATS arises from the depolarization of the resting membrane potential caused by a decrease in IK1.12 The depolarized resting membrane potential means that sodium channels, which are responsible for initiating APs, are unable to fully recover from inactivation, leading to a less excitable membrane and less forceful muscle contraction.12 The mechanisms underlying the skeletal abnormalities seen in ATS have not been fully explained. Potential factors include impaired function of osteoclasts, cells which regulate bone growth, or disruption of the bone morphogenetic protein signaling cascade.12

THE POSTULATED EXPERIMENTAL “PING–PONG” MECHANISM IN THE HIS–PURKINJE SYSTEM TO EXPLAIN BVT

Baher et al78 evaluated a “ping–pong” experimental model of reciprocating bigeminy to explain BVT. In human heart studies, alternating ectopic foci originating from the distal His–Purkinje system in both ventricles were attributed to the origin of BVT. They constructed a 2D anatomic model of rabbit ventricles with a simplified His–Purkinje system, in which different sites in this location had different HR thresholds for DAD-induced bigeminy. The authors speculated that the full spectrum of BVT can be accounted for based on the known properties of DAD-triggered arrhythmias. In the case of a single arrhythmic focus in the distal His–Purkinje system or ventricular myocardium, a DAD-triggered extrasystole alternated with each sinus beat in bigeminy. On the other hand, when 2 foci are involved, ventricular bigeminy results from the foci activating each other like a ping–pong mechanism. In rare cases of torsade de pointes, 3 or more foci develop bigeminy. When bigeminy progresses to repetitive DADs, a run of TA is generated, and the site with the most rapid rate of TA overdrives the other slower sites, causing a monomorphic VT.

Ventricular fibrillation is registered when 2 mechanisms operate concomitantly: reentry and DAD TA.78

ECG characterization of BVT consists of a regular VT, HR between 140 and 200 bpm, complete RBBB pattern, sudden change of QRS morphology by changing of the SÂQRS, successively from beat to beat, SÂQRS in the frontal plane with differences close to 180°; one beat presents QRS axis between –60° and –90° (complete RBBB + left anterior fascicular block) and the following between +120° to +130° (complete RBBB + left posterior fascicular block), occasionally there is alternating RBBB and LBBB morphology. The origin of the tachycardia is located near the His bundle bifurcation. This suggests a single focus at the interventricular septum with 2 exit sites, depolarizing the right and left ventricles in an alternate fashion.55 Two sets of fairly constant and alternating VA intervals can be recorded. This fact is consistent with 2 ventricular circuits used alternatively. It is postulated that the tachycardia is due to macro-reentry involving the 2 fascicles of the left branch. Reentry may be a possible mechanism in some cases of BVT.

An association in the ECG of sinus bradycardia + normal QTc interval + stress-related BVT or polymorphic VT in the absence of apparent structural heart disease are clues for the diagnosis of CPVT.79–81

DIFFERENTIAL DIAGNOSIS

The differential diagnosis for a prolonged QT interval includes other forms of LQTS, such as Romano–Ward, a LQTS with AD or de novo inheritance, in which only the electrical activity of the heart is affected, without involving any other organs, but with syncope and/or sudden cardiac death. It is interesting to mention that Priori et al82 provided the first evidence of a recessive form of isolated LQTS and indicated that homozygous mutations on KVLQT1 do not invariably produce the Jervell and Lange–Nielsen syndrome. Other differential diagnostic alternatives are the Jervell and Lange–Nielsen syndrome, in which a prolonged QT interval is combined with congenital deafness, and the Timothy syndrome in which a prolonged QT interval is combined with abnormalities in the structure of the heart, in addition to the autism spectrum disorder.83

The frequent extrasystoles and BVT seen in ATS can also occur in CPVT.84

ATS and CPVT are characterized by BVT. Inoue et al85 evaluated the diagnostic value of the exercise stress tests for the differential diagnosis between ATS1 and CPVT. The study included 26 ATS1 and 25 CPVT patients, and clinical and ECG characteristics, responses of VAs to exercise testing, and the morphology of VAs between ATS and CPVT patients were compared. VAs were more frequently observed at rest in ATS compared with CPVT patients at peak exercise and were suppressed in ATS, whereas they were increased in CPVT patients. The authors verified that in patients with ATS1, VAs with a RBBB pattern were frequently observed at baseline and suppressed at peak exercise, and increased at recovery. In contrast, exercise provoked VAs with mainly LBBB, but also RBBB morphology in patients with CPVT. In addition to clinical and baseline ECG assessments, exercise testing might be useful for making the diagnosis between ATS and CPVT. These observations would provide some useful clinical guidance to those who might not have fast access to genetic results, which are expensive and take several months to get results.85

The intermittent weakness seen in ATS also occurs in other forms of periodic paralysis – hypokalemic periodic paralysis and paramyotonia congenita.34

FUNCTIONAL TESTING

Electromyography helps in the evaluation of neuromuscular diseases, especially in assessing peripheral nerve disease, by providing a physiologic assessment of the peripheral nerve, muscle, neuromuscular junction, dorsal root ganglion cell, and anterior horn cell. In ATS1, nerve conduction studies and electromyography are normal between episodes without myotonia. A more sensitive electrophysiologic study with a long-exercise protocol may reveal an immediate post-exercise increment followed by an abnormal decrement in the compound motor AP amplitude (>40%)86 or area (>50%) 20–40 minutes post-exercise.87,88 In a study of 11 individuals with ATS, 82% met long-exercise amplitude decrement criteria for abnormal testing.89

Twenty-four hour Holter monitoring is important to document the presence, frequency, and duration of VT and the presence or absence of associated symptoms.

MANAGEMENT

ATS cannot be cured; however, many symptoms, such as blackouts due to abnormal heart rhythms, or periodic paralysis, can be successfully treated with medication or implantable devices. The rarity of the condition means that many of these treatments are based on consensus opinion as there are too few patients to conduct adequately powered clinical trials.12 Delannoy et al36 reported that despite severe clinical presentation with a very high rate of VAs, the prognosis of ATS1 is relatively good with treatment involving β-blocker therapy and flecainide to prevent severe arrhythmic events.36 However, some Japanese KCNJ2-positive patients had aborted cardiac arrest in adulthood. The authors concluded that KCNJ2 positive probands should be followed attentively even after childhood.90

Fernlund et al4 identified a novel mutation in the KCNJ2 gene (phenotype of 4 amino acids in the first transmembrane domain of the KCNJ2 protein (c.271 282del12 (p.Ala91 Leu94deletion) associated with malignant arrhythmic events. Krych et al10 observed that the treadmill test triggered extrasystoles and BVT similar to CPVT. A higher risk of arrhythmia, syncope, and/or cardiac arrest was associated with the presence of micrognathia, periodic paralysis, and prolonged Tpeak–Tend time. In both ATS1 with K897T mutation, the parameter was always prolonged: 139 ± 29 versus 97 ± 19 ms in mutation carriers versus noncarriers (normal value is ≤94 ms in V5 precordial lead). These features suggest that the K897T mutation may contribute to the occurrence of syncope.10

Medications known to prolong QTc/QU intervals, such as inhaled salbutamol, may exacerbate cardiac arrhythmias, while thiazide and other K+-wasting diuretics may provoke drug-induced hypokalemia and could aggravate QTc/QU interval prolongation. Medications, such as sotalol and amiodarone, which further prolong the QT interval, should be avoided as they can promote abnormal heart rhythms.12 Lists of medications associated with prolongation of the QTc interval can be found on the Internet.91 Drugs such as furosemide and bendroflumethiazide that reduce blood K+ levels should also be avoided as they can worsen the tendency to periodic paralysis and arrhythmias.12 Conversely, K+-containing supplements may be helpful.12 Very strenuous or competitive sports should be discouraged as these may increase the risk of arrhythmias, although gentle exercise should be encouraged.83

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

Sodium channel blockers can be useful as additional pharmacologic therapy for patients with a QTc interval greater than 500 ms. Only a few cases involving the use of flecainide alone have been reported in case of intolerance to β-blockers.44 An intravenous flecainide challenge test may be useful in predicting the efficacy of oral flecainide.92 Combined β-blocker and flecainide therapy was efficient to prevent severe arrhythmic events.36

In patients with ATS with drug-refractory VAs, additional treatment with oral flecainide (100 mg/m2 daily) should be considered, and a preceding intravenous infusion test of flecainide should be performed to promptly confirm the drug’s effect. Pellizzón et al93 documented that flecainide can be effective in controlling incessant BVT-induced cardiomyopathy associated with ATS1. Recently, Ergül et al94 observed that the number of extrasystoles was significantly reduced with this drug, and VT events totally disappeared.94 Unrefined categorization and overlapping of symptoms between ATS and CPVT create a problem for physicians dealing with inherited arrhythmia disorders. These observations about the efficacy of flecainide were confirmed by Barajas-Martinez et al95 and Kalscheur et al.96 They recommended the use of this drug in cases of failure or intolerance to β-blocker therapy.

The mechanism by which flecainide suppresses VAs is decreased DAD. Inhibition of the Na+ channel may directly suppress TA and/or indirectly inhibit Na+/Ca2+ exchange, resulting in a reduction of intracellular Ca2+ overload and decreased DAD. Hypokalemia due to diarrhea, a prolonged QTc interval with a prolonged terminal portion of the T wave, and a large U wave accentuated by flecainide may cause cardiac arrest.

In cases with low response to antiarrhythmic medication, refractory arrhythmia or drug intolerance, and in survivors of a cardiac arrest with recurrent syncope or sustained, symptomatic VT, implantable cardioverter-defibrillator implantation should be considered.74

During pregnancy, a reduction in extrasystoles is observed. Hemodynamic or hormonal changes related to gestation may have favorable effects on cardiac repolarization. Alterations in gene regulation, ion channel function, and/or electrolyte balance may also play a role. Further clinical and cellular studies are needed to make more definitive conclusions. Given the paucity of evidence pertaining to prenatal and antenatal care of the patient with ATS, a sensible and cautious multidisciplinary approach is necessary during pregnancy and delivery. Although a potentially elevated risk must be anticipated, as has been reported in the postpartum period in patients with LQTS,97 an uneventful course is most common in ATS.98

Periodic Paralysis

The administration of oral potassium (20–30 mEq/L) every 15–30 minutes (not to exceed 200 mEq in a 12-hour period) if the serum K+ concentration is less than 3.0 mmol/L, until the serum concentration normalizes, is recommended. If a relative drop in serum K+ within the normal range causes episodic paralysis, an individual K+ replacement regimen with a goal of maintaining serum K+ levels in the high range of normal can be considered. If serum K+ concentration is high, ingesting carbohydrates may lower serum K+ levels. Mild exercise may shorten or reduce the severity of the attack. Periodic paralysis may be improved by taking carbonic anhydrase inhibitors such as acetazolamide.12 Amiodarone, flecainide, and calcium antagonist have also been proposed.99,100

CONCLUSIONS

ATS is a very rare AD or de novo multisystemic genetic syndrome characterized by the triad of periodic paralysis, VAs, and dysmorphic features of the face, head, limb, and thorax. The hallmark of VA is BVT as a consequence of prolonging the QUc interval with normal or minimally prolonged QTc. To date, there is no consensus on a therapeutic approach, but β-blockers, flecainide combined or alone, may be effective for VAs, and the implantation of a cardioverter-defibrillator may be necessary in malignant variants. Spironolactone, amiloride, and potassium supplements can improve the effects of periodic paralysis.

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Keywords:

Andersen–Tawil syndrome; developmental abnormalities/dysmorphism; K+-sensitive periodic paralysis; QU interval; bidirectional ventricular tachycardia

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