Andersen-Tawil syndrome (ATS), which is sometimes named long QT syndrome type 7, is
a rare genetic potassium channelopathy combining frequent and sometimes serious ventricular
arrhythmias (VA), a prominent U-wave in electrocardiography, periodic paralysis and
various dysmorphic features. In most ATS patients a mutation in the KCNJ2 gene was
found (encoding potassium channel Kir2.1) [1–3]. Since ATS is a rare disease, no evidence-based
recommendations for VA management are available either. Successful β-blocker, calcium
channel blocker or flecainide medication has been described in many cases [1, 2, 4–6].
However, limited data on propafenone treatment and its efficacy in ATS are available
[7].
We present an 18-year-old woman with genetically confirmed ATS (G146R mutation of
KCJN2 gene) in whom severe VA were observed since her childhood. She presented typical
ATS dysmorphic features (hypertelorism, mandibular hypoplasia and syndactyly) and
suffered from periodic paralysis. Andersen-Tawil syndrome was also diagnosed in her
mother (the same mutation), but she presented only slight dysmorphic features and
no VA. The patient’s father and her two brothers were healthy. At presentation the
patient’s echocardiography was normal. In many Holter recordings asymptomatic typical
VA were observed including frequent pairs, bigeminy or trigeminy and non-sustained
bidirectional ventricular tachycardia (BVT), up to 50–60 thousand ventricular beats
daily. After VA diagnosis, various antiarrhythmic drugs were prescribed and finally
flecainide was found to be the most effective, with significant VA reduction to 5–10
thousand beats daily and 5–20 short BVT. Due to logistic problems with flecainide
supply in our country, we decided to replace flecainide with readily available propafenone,
which is also a Vaughan-Williams class IC antiarrhythmic agent and is registered for
VA treatment. After admission to our department the patient received propafenone 150
mg t.i.d. and metoprolol succinate 50 mg daily with a small increase of VA in initial
clinical observation. Unfortunately, subsequent Holter recordings showed stable intensified
VA (15–20 thousand beats daily), and a substantial increase of the number, length
and heart rate of BVT (400–800 episodes daily, up to 20–25 s). Typical BVT and standard
ECG of our patient are presented in the Figure 1. Moreover, the patient became pregnant
with further exacerbation of VA (especially BVT), so we decided to reintroduce flecainide
treatment 100 mg b.i.d., with dramatic VA reduction (6 thousand beats, 40 very short
BVT only). After propafenone cessation for 2 days the patient received only β-blocker
and further intensity of VA with 1300 episodes of BVT was observed then. It is indirect
evidence that propafenone did not exert a proarrhythmic effect, but it lacked sufficient
efficacy in our patient.
Figure 1
A – Standard ECG. Sinus rhythm 64 bpm. QT/QTc intervals 430/450 ms. Distinct U wave
in leads V2–V3. B – 3-channel 24-hour Holter monitoring. Nonsustained bidirectional
ventricular tachycardia (BVT)
Various genetic factors (over 40 mutations and 3 deletions of the KCNJ2 gene) and
also extremely low prevalence of ATS (approx. 1 per 1 million population) cause that
knowledge of this disease is based on observations of small groups of patients and
case reports only. The present woman is one of 15 genetically confirmed ATS subjects
who have been observed and treated in our departments [3]. Serious and severe VA (especially
BVT and torsades de pointes leading to ventricular fibrillation) may be a cause of
sudden cardiac death (SCD). However, the risk of SCD in all ATS patients is relatively
small, and most often it is estimated at below 3–10% of cases [1, 2, 8]. Successful
antiarrhythmic treatment in our patient was important not only due to SCD risk, but
also due to a temporary decrease of left ventricular ejection fraction during intensified
VA, which was observed in her childhood. As ATS is a rare disease, no definitive recommendations
for VA management are available. It seems that β-blocker treatment is of clinical
value, but successful calcium channel blocker medication and a combination of flecainide
plus β-blockers have also been described [1, 2, 4, 5]. Unfortunately, pharmacological
treatment is not beneficial in many patients. In some ATS cases implantation of a
cardioverter-defibrillator is indicated, but it is controversial [8]. Similarly to
other channelopathies, ablation attempts fail in many cases.
We tried to treat our patient with propafenone because it is a similar agent to flecainide
– similar, but not the same. In contrast to flecainide, propafenone has additional
clinically significant β-blocker activity. Prolonged action potential duration and
efficacy of standard propafenone treatment may also depend on metabolic variability
among consecutive subjects (fast and slow metabolizers). On the other hand, flecainide
additionally demonstrates a minor calcium channel blockade effect, and it has affinity
for the open state sodium channel only [9–11]. We did not assess concentrations of
propafenone and its active metabolites. However, our patient was a rather slim woman
(body mass approx. 50 kg), and we were afraid to prescribe larger doses than 450 mg
daily. We do not conclude that propafenone will not be effective in all ATS patients
either. It is worth noting that some KCNJ2 mutations are associated with extremely
high risk of severe VA [12]. Maybe a type of mutation influences the response to the
prescribed type of drug too?
In conclusion, we present the first case of ATS in a patient with severe and potentially
life-threatening VA who was treated with propafenone. However, this therapy was ineffective,
and flecainide had to be reintroduced, with substantial improvement.
Conflict of interest
The authors declare no conflict of interest.