Andrew H. Smith, M.D., Frank A. Fish, M.D., and Prince J. Kannankeril,
M.D., M.S.C.I
From The Department of Pediatrics, Vanderbilt University School of
Medicine, Nashville, TN
Address for
correspondence: Prince J. Kannankeril, MD, Assistant Professor
of Pediatrics, Division of Pediatric Cardiology, Vanderbilt Children’s
Hospital, 2200 Children’s Way, Suite 5230, Nashville, TN 37232-9119.
Email: prince.kannankeril@vanderbilt.edu
Dr. Kannankeril is supported by a Vanderbilt University School of
Medicine Clinician Scientist Award, and by the National Heart, Lung,
and Blood Institute (HL076264)
Abstract
Andersen-Tawil
syndrome (ATS) is a rare condition consisting of ventricular
arrhythmias, periodic paralysis, and dysmorphic features. In
2001, mutations in KCNJ2, which encodes the α subunit of the potassium
channel Kir2.1, were identified in patients with ATS. To date,
KCNJ2 is the only gene implicated in ATS, accounting for approximately
60% of cases. ATS is a unique channelopathy, and represents the
first link between cardiac and skeletal muscle excitability. The
arrhythmias observed in ATS are distinctive; patients may be
asymptomatic, or minimally symptomatic despite a high arrhythmia burden
with frequent ventricular ectopy and bidirectional ventricular
tachycardia. However, patients remain at risk for
life-threatening arrhythmias, including
torsades de pointes and
ventricular fibrillation, albeit less commonly than observed in other
genetic arrhythmia syndromes. The characteristic heterogeneity at
both the genotypic and phenotypic levels contribute to the continued
difficulties with appropriate diagnosis, risk stratification, and
effective therapy. The initial recognition of a syndromic
association of clinically diverse symptoms, and the subsequent
identification of the underlying molecular genetic basis of ATS has
enhanced both clinical care, and our understanding of the critical
function of Kir2.1 on skeletal muscle excitability and cardiac action
potential.
Keywords: Arrhythmias; Genetics; ion channels;
Andersen-Tawil syndrome
Introduction
Andersen-Tawil
syndrome describes a rare condition consisting of ventricular
arrhythmias, potassium-sensitive periodic paralysis, and developmental
anomalies.
1,2
While two cases of familial periodic paralysis associated with
ventricular ectopy were first described in 1963,
3
the suggestion of a potential syndromic association was not proposed
until 1971, when Ellen Andersen and colleagues described the
characteristic triad in an 8 year-old dysmorphic boy who experienced
episodes of muscle weakness and ventricular extrasystoles.
4 Nearly a quarter of a
century later, 10 previously-described cases were reviewed, in addition
to 4 new patients in 3 kindreds, who appeared to inherit the condition
predominantly in an autosomal dominant pattern. Noting for the
first time the phenotypically heterogenous nature of this disease, this
was also the first report to ascribe the name of Andersen’s syndrome to
this constellation of symptoms.
1
Subsequently, the syndrome was renamed Andersen-Tawil Syndrome (ATS) in
recognition of the contributions of Dr. Rabi Tawil, who developed
diagnostic criteria and refined understanding of this entity.
5
Following its
initial characterization, significant advances have improved our
understanding of the genetic basis and molecular aspects of ATS.
In the seminal paper by Plaster et al,
2
linkage analysis in a large kindred revealed a locus corresponding to a
genetic region of over 40 cM on chromosome 17q23. With the notion
that both the periodic paralyses and abnormalities in myocardial cell
repolarization were associated with ion channel mutations, so-called
channelopathies, the 3 ion channel genes within the linked region
(KCNJ2, CACNG1, and SCN4A) were suitable candidate genes. SCN4A
was known to underlie periodic paralysis without heart or developmental
problems,
6 and the CACNG1
gene product was not detected in heart. Due to the known function
and expression pattern of Kir2.1, the protein encoded by KCNJ2, it was
considered an excellent candidate gene for ATS. Eight different
mutations in KCNJ2 were initially identified in ATS patients, and
functional characterization of 2 of the mutations revealed dominant
negative effects on channel function. These findings demonstrated
that ATS mutations in KCNJ2, which encodes the Kir2.1 channel α
subunit, appear to markedly impair its vital role in stabilizing
resting membrane potential and mediating the terminal repolarization
phase of the action potential, resulting in a predisposition to
ventricular arrhythmias through mechanisms discussed below.
We will review
the clinical manifestations of Andersen-Tawil syndrome, including
distinguishing historical, physical examination, and electrophysiologic
findings. We will discuss the genetic and molecular aspects of ATS, and
will address the characteristic heterogeneity at both the genotypic and
phenotypic levels. Finally, we will explore various therapies
devised to address the primary cause of morbidity and mortality in ATS,
namely the propensity for life-threatening ventricular arrhythmias.
Clinical Manifestations
Since the
initial report of Andersen-Tawil syndrome, literature has emerged
emphasizing the inconsistencies in phenotypic expression and disease
severity.
7 Such
variability has been described among kindreds, as well as among members
of the same families.
8
This variability has made the diagnosis of ATS difficult. In
fact, half of the new patients described in the initial paper proposing
the term “Andersen’s syndrome” were diagnosed only after repeated
evaluations.
1
Unpredictability is seen not only in dysmorphic characteristics, but
electrophysiologic manifestations as well. Although ATS is
inherited in an autosomal dominant pattern, given its heterogenous
expressivity, a family history of associated characteristics may not be
elicited. In fact, there is up to a 20% incidence of
non-penetrance in individuals with KCNJ2 mutations. Additionally,
up to 40% of patients with ATS do not have KCNJ2 mutations, further
confounding the ability to utilize genetic screening as a diagnostic
tool.
5
Dysmorphic
features
Appreciation
of dysmorphic manifestations comprise one of the three fundamental
elements in the evaluation of ATS. Features initially described
included short stature, hypertelorism (wide-set eyes), low-set ears,
palatal defects, mandibular hypoplasia, single palmar crease,
crytporchidism, and slight bilateral ptosis.
4
In a recent series of 36 KCNJ2 mutation carriers, 78% had at least two
dysmorphic features, the most common being clinodactyly (permanent
medial or lateral curvature of a finger or toe, seen in 64%) and
mandibular hypoplasia (44%).
8
Other features described have included scoliosis, hyperthyroidism,
vaginal atresia, and unilateral dysplastic kidney; structural
cardiovascular anomalies such as a bicuspid aortic valve with or
without associated coarctation, and valvular pulmonic stenosis have
been reported as well.
9
Also noted in one series was that the severity of facial dysmorphism
did not correlate with the severity of cardiac or skeletal muscular
involvement.
10
Periodic
Paralysis
Periodic
paralysis serves as another key element to the clinical diagnosis of
ATS. Historically, the age of onset of weakness is highly
variable, though typically within the first two decades of life.
10 These episodes typically will
present before any cardiac symptoms, and are usually manifested
following periods of prolonged physical exertion. Examination
reveals a muscular weakness that is proximal in nature, and may be
associated with muscle wasting. Attacks have been demonstrated in
patients with varying serum potassium levels (either hypo-, hyper-, or
normokalemia), though levels have been found to remain consistent among
an individual kindred.
2
Potassium challenges have been found to at times either induce or even
successfully treat episodic weakness.
1,10 Noted in one kindred was a
sex-specific expressivity, with periodic paralysis appearing to
segregate as an autosomal dominant trait only among males.
9 Additional findings have included
markedly elevated serum creatine kinase levels, normal electromyogram,
and tubular aggregates or minimal mypoathic changes apparent on
pathologic examination of skeletal muscle biopsy.
1,8
Cardiac
Manifestations
True to its
variability in phenotypic expression, there exists a wide range of
electrophysiologic manifestations in ATS. Some patients have QT
interval prolongation, while others demonstrate normal QT
intervals. Prominent U waves in the anterior precordial leads are
common in ATS.
11
Although U waves can be observed in normal individuals at low heart
rates or in hypokalemic states, these are described in ATS patients at
higher heart rates, suggesting that this may represent a manifestation
of disease rather than a normal variant.
8
Associated arrhythmias range from isolated premature ventricular beats
to complex ventricular ectopy and polymorphic ventricular tachycardias
such as bidirectional ventricular tachycardia or less commonly
torsades de pointes (see
Figure 1).
2,11,12 Complete
right bundle branch block, left bundle branch block, bifasicular block,
and first-degree atrioventricular block have also been described in
patients with known KCNJ2 mutations.
8,11 Both nonfatal cardiac arrest
with documented torsades de pointes, and sudden death, thought to be
less common relative to its long QT syndrome (LQTS) counterparts, have
also been reported.
13
Sex-specific expressivity of the arrhythmia phenotype has been
described in 1 family, where 13 of 16 female carriers, but no male
carriers, demonstrated a history of ventricular arrhythmias.
9 While gender differences in
cardiac repolarization are well described but not completely understood,
14 hormonal modulation of arrhythmia risk
is suggested by our observation that arrhythmias in ATS may be
quiescent during pregnancy.
Figure 1. Ambulatory ECG
tracings of ventricular arrhythmias in Andersen-Tawil Syndrome.
The top panel recorded in a newborn boy with the G144S mutation in
KCNJ2 shows sinus rhythm with premature ventricular beats in a
bigeminal pattern. The middle and bottom panels recorded in the
boy’s mother with the same mutation show runs of polymorphic and
bidirectional ventricular tachycardia.
The
association between ATS and a prolonged corrected QT interval has
recently been called into question. Citing its relationship to other
disorders of myocellular repolarization, predisposition to ventricular
arrhythmias, and the purported presence of a prolonged QT
interval in 71% of all KCNJ2 mutation carriers, it had been suggested
that ATS be classified as LQT7.
8
A systematic assessment of ATS patient electrocardiograms was recently
completed with conflicting results. Specifically, in ATS patients
with and without KCNJ2 mutations, median corrected QT intervals were
minimally longer (20 ms) than controls, remaining within the normal
range (median, 440 ms); in fact, only 17% of ATS patients in this
series had a QTc of over 460 ms. Additionally, it was noted that
those patients possessing KCNJ2 mutations appeared to have a
distinctive electrocardiographic phenotype, consisting of a prolonged
terminal T wave downslope, a widened T-U wave junction, as well as
biphasic and enlarged U waves; such findings were not evident in either
ATS patients lacking KCNJ2 mutations or in healthy controls.
Accordingly, some now recommend that patients with KCNJ2 mutations be
classified as ATS1, rather than LQT7.
11
A
well-characterized feature of ATS is its propensity for ventricular
arrhythmias. In addition to isolated premature ventricular beats,
ventricular tachycardias (VT) involving a beat-to-beat variability in
axis (polymorphic ventricular tachycardia), such as bidirectional
ventricular tachycardia and torsades de pointes, have been described.
2,12,15
Torsades de pointes and
its potential for progression to life-threatening ventricular
fibrillation is a well-known complication associated with the
prolongation of the plateau phase of the action potential seen in
congenital and acquired long QT syndromes.
16,17 Bidirectional ventricular
tachycardia is a distinct form of polymorphic VT, characteristically
associated with intracellular calcium overload and seen in
catechecholaminergic polymorphic ventricular tachycardia (CPVT) and
digitalis toxicity.
12,18,19 A relationship to intracellular
calcium overload and Na+/Ca2+-mediated triggering of arrhythmic
activity has been proposed in ATS.
8
Bidirectional VT, though
rare, has been described extensively in association with ATS.
2 Indeed, bidirectional ventricular
tachycardia in the absence of other causes should prompt a thorough
search for other features of ATS in the patient and kindred. In a
cohort of 36 carriers of KCNJ2 mutations, a relatively low rate of
syncope and cardiac arrest was described, despite a high arrhythmia
burden. Ventricular arrhythmias were noted in 88% of patients,
with nonsustained VT present in 65% of probands, and bidirectional VT
seen in 18% of probands. Only 2 patients experienced nonfatal
cardiac arrest (1 with documented
torsades
de pointes) and there were 4 episodes of syncope.
Additionally, there were no cases of sudden cardiac death, nor was
there a reported family history of sudden death among subjects.
8 Interestingly, the incidence of
symptoms such as syncope in this cohort was less than 20%, markedly
lower than the 63% and 46% reported in LQT1 and LQT2 syndromes
respectively.
20
As ATS is a
rare disorder, there exists no literature currently which correlates
particular genotypes or clinical features with an assessment of risk
for development of life-threatening ventricular arrhythmias and sudden
death. While such reports of sudden death are rare in the
literature, ATS patients remain predisposed to the development of
polymorphic ventricular tachycardias such as bidirectional VT and
torsades de pointes; with their potential for deterioration to
ventricular fibrillation and hemodynamic collapse. These patients
consequently remain at an increased risk for sudden cardiac death
relative to the general population.
Diagnosis
Given the heterogenous nature of the clinical manifestations of
Andersen-Tawil syndrome, a definitive diagnosis at times is
elusive. Manifestation of at least two phenotypic classes
(skeletal, cardiac, or developmental) has been thought to be necessary
for diagnosis of ATS.
8
While some patients may manifest aspects consistent with all three
classes of the clinical anomalies, others, (including those with known
KCNJ2 mutations) may manifest only a single phenotypic
classification. In these instances, some authors have suggested
diagnosing such patients should they have a substantial family history.
5 Noting that to date, about 60% of
Andersen syndrome patients are found to have mutations in Kir2.1,
screening for KCNJ2 mutations also provides an increasingly valuable
tool in either confirming or establishing diagnosis in a phenotypically
heterogenous condition.
Molecular manifestations
Kir2.1
Mutations in
KCNJ2, which encodes the α-subunit of Kir 2.1, an inwardly-rectifying
potassium channel, have been identified as the genetic defects
underlying the clinical phenotype of Andersen-Tawil syndrome.
2 The Kir2 family of potassium
subunits is expressed in both heart and skeletal muscle, and is the
first disordered channel associated with phenotypic manifestations
within both skeletal and cardiac muscle.
21,22 Kir2.1 subunits form a 427 amino
acid protein, with 2 transmembrane domains and an extracellular pore
forming loop containing the GYG amino acid sequence responsible for
determining channel selectivity for potassium. The Kir2.1 channel
functions as an inward rectifier, its conductance changing with voltage
differences across the membrane. The term inward rectification
indicates that while there is an inward flow of potassium current at
hyperpolarized potentials, the same voltage gradient with
depolarization produces much less outward potassium flow. At
potentials more negative to – 20 mV, the Kir channels increasingly
permit potassium efflux, providing a current which mediates the
terminal phase of repolarization. The current provided by inward
rectifiers such as the Kir2.1 channel, termed IK1, has consequently
been shown to play a role in the determining cardiac excitability, and
to “set” the resting potential.
23,24
Kir2.1:
Molecular pathology
Four
individual Kir2.1 proteins co-assemble to form a functional tetrameric
channel. While injection of normal Kir2.1 cRNA into oocytes
results in potassium currents with strong inward rectification,
injection of mutant (D71V and R218W) cRNA into oocytes resulted in no
detectable current.
2
These results raise 2 possibilities: the mutant proteins either failed
to co-assemble, or assemble normally but impair channel function.
The latter was suggested by the finding of “dominant negative”
suppression of channel function; > 50% reduction in current with
coexpression of normal and mutant Kir2.1 subunits. It is proposed
that mutant proteins assemble with normal proteins into tetrameric
channels, but the presence of 1 or more mutants in the channel is
sufficient to disrupt current flow. Assuming random expression
and co-assembly, only 1 out of every 16 channels would consist of 4
normal subunits, and function normally, while 15 of 16 would harbor at
least 1 mutant protein. Indeed, coexpression of the D71V mutant
cRNA with normal cRNA resulted in a current approximately 1/16
th
of normal current.
While other
mutations have been described involving the external pore forming loop
of Kir2.1,
7 mutations in
KCNJ2 impairing channel interactions with
phosphatidylinositol 4,5-bisphosphonate (PIP
2) are thought
to play a significant role as pathogenic mechanism in ATS.
25 PIP
2 is a
membrane-bound second messenger which activates Kir2.1, among other
inward-rectifiers, and promotes an open-channel position.
5 Also, in vitro it was demonstrated
that in general (and especially with the previously described R218W
mutation), these mutations resulted in impaired channel- PIP
2
interactions, affecting whole-cell current and marked decreases in
open-channel probability.
25
Consequently, impairments in PIP
2 –mediated channel function
would result in an increase in mean closed time, as has been described,
resulting in a decrease in channel activity and manifestation of
disease phenotype.
Effects of
impaired IK1
Decelerates
repolarization/prolongs action potential duration/depolarizes,
destabilizes resting membrane potential
The effects of
reduced I
K1 in a theoretical model of rabbit ventricular
myocyte demonstrated a prolongation of the terminal phase of the action
potential.
8 Reductions
in extracellular potassium concentrations along with decreases in I
K1
were also associated with development of “terminal-phase” early after
depolarizations (EADs), leading to spontaneous action potentials and
providing a possible explanation for the frequent ventricular ectopy
seen in patients with ATS. The term “terminal-phase” was used to
distinguish the observed phenomena from the typical EAD’s seen in LQTS
that arise from the plateau or early repolarization phase of the action
potential. Interestingly, also noted was the sodium-calcium
exchanger-dependent development of delayed after depolarizations, much
like those seen with digitalis toxicity. This may underlie the
risk for bidirectional VT that is often observed in ATS.
Using
adenoviral gene transfer techniques, Miake and colleagues were able to
further delineate the in vivo role of I
K1 in cardiac
repolarization, studying isolated ventricular myocytes from adult
guinea pig with both augmented and diminished I
K1 expression.
26 “Dominant negative” reduction in
I
K1 was achieved by over expression of mutant Kir2.1with the
GYG potassium selectivity motif replaced with AAA. This resulted
in prolongation of action potential duration (APD), deceleration of
phase 3 repolarization, and depolarization of the resting membrane
potential (RMP). Conversely, over expression of human Kir2.1 with
a consequent increase in I
K1 led to significant APD
shortening with hyperpolarization of RMP and acceleration of phase 3
repolarization.
Clinical
application of the recent understanding of the role of Kir2.1 and its
corresponding current, I
K1, continues to evolve.
Patients with ATS and KCNJ2 mutations demonstrate a distinct change in
U wave morphology, an electrocardiographic characteristic associated
with frequent premature ventricular beats and nonsustained VT,
potentially demonstrating an increased vulnerability to ventricular
arrhythmia.
11
Mutation-induced reductions in I
K1 have been proposed to
lead to a prominent U wave morphology and ventricular ectopy through an
increase in transmural dispersion of repolarization, leading to action
potential duration changes that vary in degree from one region of
myocardium to another, and potentially serving as the substrate for
reentrant arrhythmias. Interestingly, the gain-of-function
mutations in KCNJ2 and resulting increases in I
K1 have also
recently been correlated with disease. The resulting decreases in
action potential durations leads to accelerated atrial and ventricular
repolarization characteristic of the short QT syndrome. In the
form of short QT syndrome (SQT3) associated with a KCJN2 mutation,
ventricular fibrillation has been observed.
27
Molecular
Genetics
ATS occurs
sporadically, or is inherited in an autosomal dominant manner.
Mutations in KCNJ2 were the first described as responsible for the
phenotype of ATS. Kir2.1 subunits, encoded by KCNJ2, combine to
form tetrameric channels with additional Kir2.1 subunits,
28 or with other subunits of the Kir2.x
subfamily.
29
Mutations in KCNJ2 have been demonstrated to impair Kir2.1 channel
function usually through a mechanism of dominant negative suppression.
30 The dominant-negative nature of
ATS mutations has been well-described, whereby heterogenous expression
of wild type Kir2.1 with any number of mutant Kir2.1 subunits results
in a loss of current.
2,8,30 Also demonstrated was the
ability of mutant Kir2.1 to exert dominant-negative suppressive effects
upon other members of the Kir2.x subfamily, possibly serving as an
explanation for the interfamilial phenotypic variations in expressivity.
29
Between 6-20 %
of individuals with identified KCNJ2 mutations appear phenotypically
normal (non-penetrant).
2,5,7-9 Additionally,
approximately 30-40% of patients with ATS do not harbor KCNJ2 mutations.
5,8 In the first
demonstration of a relationship between KCJN2 mutations and ATSs, 3 of
16 families examined had no mutations in the coding regions of KCNJ2,
with no apparent phenotypic differences in those with KCNJ2 mutations
and those without.
2
Several mechanisms for this genotypic heterogeneity have been proposed,
including mutations in KCNJ2 regulatory proteins, and mutations in
other members of the Kir2.x subfamily, as these subunits assemble in
heterotetramers to form functional channels.
29
Treatment
Therapy for
ATS is directed toward its phenotypic manifestations which lead to
significant morbidity, namely associated episodic weakness and most
importantly its association with life-threatening ventricular
tachyarrhythmias. From initial reports, therapies such as oral
potassium supplementation, sodium restriction, spironolactone, and
acetazolamide have anecdotally been shown to ameliorate symptoms of
weakness.
1,3,10,31 We have obserevd improvement
with oral contraceptive therapy, with exacerbation of weakness after
discontinuation in a female patient with ATS. Unfortunately,
perhaps due to the genotypic and phenotypic heterogeneity in disease,
in concert with erratic and paradoxical exacerbation of symptoms with
therapy, no therapeutic standards exist to date.
While the
cardiac sequelae of ATS hold the greatest potential for morbidity and
mortality, they remain the most problematic in devising effective
medical therapeutic options. Given the phenotypic heterogeneity
that complicates diagnosis, this variability also plays a role as a
complicating factor in effective risk stratification. The most
concerning aspect of ATS, paroxysmal ventricular tachycardia leading to
syncope or ventricular fibrillation with cardiac arrest, is only
infrequently inducible with invasive electrophysiologic study.
12 Recently, radiofrequency
catheter ablation targeting premature ventricular beats, which may
serve as triggers for sustained ventricular arrhythmias, has been
performed in other genetic arrhythmia syndromes, including LQTS and
Brugada syndrome.
32,33
This may be an attractive approach in ATS due to the frequent
ventricular ectopy. Initial attempts to map ventricular ectopy in
patients with ATS reveal that the ectopic beats originate from
different parts of the left Purkinje network (personal communication,
P. Sanders, 2005; see
Figure 2).
Although to date, catheter ablation in ATS has not been reported, in a
patient with arrhythmic storms, this approach could be
considered.
Figure 2.
Intracardiac electrograms during spontaneous ventricular ectopy in a
patient with Andersen-Tawil syndrome. Displayed are surface leads
I, II, III, V1, and intracardiac electrograms recorded from the
anterior left ventricle. The first sinus beat is followed by 2
successive ventricular ectopic beats, each with a different
morphology. The arrows indicate Purkinje potentials preceding the
local ventricular electrograms in sinus rhythm and the ectopic
beats. The first ectopic beat is from an adjacent Purkinje site –
hence the late Purkinje relative to the QRS. (Figure courtesy of
Dr. Prashanthan Sanders, Dr. Frederic Sacher, and Dr. Michel
Haissaguerre, Hôpital Cardiologique du Haut-Lévêque,
Bordeaux, France)
Successful
pharmacologic therapy remains elusive, lacking effectiveness in
reducing the frequency of ventricular ectopy;
12
in fact, even from early reports such therapy has been recognized to
exacerbate symptoms of weakness.
1,3 We have observed similar
phenomena: improved rhythm control but worsening weakness, or improved
muscle strength, but increased ventricular ectopy. Reports of
antiarrhythmic drug efficacy remain anecdotal, and conflicting.
While calcium channel blockers are theorized to address the proposed
arrhythmogenic substrate of intracellular calcium overload, and have
been shown to terminate bidirectional VT in ATS,
15 they have also been shown ineffective
in reducing ventricular ectopy.
12
Similarly, amiodarone has been described as a successful therapy for VT
in a patient with ATS due to the R218W KCNJ2 mutation.
31 The authors suggested a
possible pharmacogenetic link between the R218W mutation and treatment
response. However, subsequently amiodarone was implicated in
inducing
torsades de pointes in
a different ATS patient who also harbored the R218W mutation.
34
While amiodarone may exacerbate early afterdepolarizations and
predispose to TdP with its inhibition of I
K1 and I
Kr,
its effects in a given patient may not be predictable. Pacing in
combination with nicorandil was successful in treating ventricular
arrhythmias in the latter patient. Pacing, by increasing heart
rate and nicorandil, by increasing outward potassium current through
IKATP, resulted in attenuation of the prominent U wave, theoretically
reducing transmural dispersion of repolarization and reducing risk for
torsades de pointes. Beta-blockers (including propranolol,
atenolol, and sotalol) and sodium channel blockers (including
mexiletine, propafenone, and flecainide) have been described as
ineffective in select patients.
12,31,34 We have
used beta-blockers alone, and in combination with calcium channel
blockers with some success, albeit in a modest number of
patients.
Aside from
preventive measures, an intervention demonstrated to successfully and
reliably treat hemodynamically unstable ventricular tachyarrhythmias is
the implantable cardioverter-defibrillator (ICD).
35 The diagnosis of ATS itself can
be considered a class IIb indication for ICD placement, citing familial
or inherited conditions with a high risk for ventricular
tachyarrhythmias as a consideration.
36
A history of cardiac arrest due to ventricular fibrillation or VT would
be regarded as a class I indication for ICD placement in ATS, noting
that there is evidence and/or general agreement that ICD placement is
both useful and effective. Although sustained VT can also be
considered a class I indication for an ICD, many ATS patients are
asymptomatic during episodes of sustained ventricular tachycardia.
12 Until further data regarding
risk startification becomes available, it seems prudent to reserve ICD
therapy for ATS patients with a history of cardiac arrest, syncope, or
sustained rapid and/or symptomatic VT. Furthermore, ICD
programming should be tailored to minimize the risk of multiple shocks
for VT that may be well tolerated. Programming no therapy for VT,
12 or anti-tachycardia pacing rather than
shocks for VT have been advocated.
37
Conclusions
Andersen-Tawil syndrome is a rare condition with variable
expression, caused by sporadic mutations or in an autosomal
dominant
manner. Mutations in KCNJ2 which encode the inwardly rectifying
channel Kir2.1 lead to the clinically apparent phenotype of ventricular
arrhythmias, periodic paralysis, and developmental anomalies.
Marked variation in expression confounds ability to diagnose, risk
stratify, and effectively treat patients. ATS differs both on a
molecular and phenotypic level from the long QT syndromes, and it has
been suggested to abandon its determination as LQT7. Effective
pharmacologic therapy for associated ventricular arrhythmias is
lacking, prompting consideration of ICD placement or possibly catheter
ablation in high-risk patients.
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