Case presentation
An 8-year-old female patient was referred to a paediatrician for assessment of an
episode of global muscle weakness after a 100 m sprint. There was no loss of consciousness.
Proximal hip muscles and shoulder girdle weakness was noted and the possibility of
a myopathy was raised. Muscle biopsy demonstrated “ultra-structurally normal muscle
fibres”. There was indolent progression of proximal muscle weakness over the years,
with no diagnosis made.
At the age of 18 the patient experienced three episodes of transient loss of consciousness
over a two-week period. A witness described sudden “unresponsiveness and generalised
muscle twitching”; a period of confusion consistent with a post-ictal period was noted.
There was no urinary incontinence or tongue biting. No trigger was identified. Inpatient
EEG and MRI brain were normal. A further episode of transient loss of consciousness,
documented in the hospital record as ‘consistent with seizure activity’ occurred;
cardiac monitoring did not reveal an arrhythmia. A clinical diagnosis of epilepsy
was made based on the description of the episodes and lack of a symptom rhythm correlation.
The patient was commenced on sodium valproate, which prevented further episodes.
Surface electrocardiograms recorded during the admission documented asymptomatic,
frequent polymorphic ectopy Fig. 1.
The QTc was marginally prolonged at 465ms (Bazett's formula). Echocardiogram showed
no evidence of structural heart disease. An outpatient Holter monitor confirmed the
background rhythm was sinus, with episodes of non-sustained bidirectional ventricular
tachycardia and frequent multimorphological ventricular ectopy with a 25% ectopic
burden. Ectopy was suppressed completely during treadmill exercise testing. The effect
of exercise on the QT interval was not recorded. Metoprolol, verapamil, sotalol and
flecainide were sequentially tried, but were either ineffective or produced intolerable
side effects.
At the age of 23 years the patient moved interstate and was referred for review. She
had been seizure-free for 5 years. Medical background was unremarkable. Family history
was incomplete (patient had no available history from the paternal side. No abnormalities
were noted on the maternal side). Physical examination revealed short stature, mandibular
hypoplasia, hypertelorism and a broad nasal root. Neurological assessment demonstrated
a waddling gait, with inability to rise from a sitting position without assistance.
No fasciculation or myotonia was evident. Marked proximal upper and lower limb girdle
weakness, Medical Research Council (MRC) 2–3/5, was found associated with hypotonia.
Distal strength was largely preserved. Reflexes were symmetrically depressed. Cardiovascular
examination found an irregular pulse. ECG showed frequent polymorphic ectopy as before.
A channelopathy for the cause of her frequent ventricular ectopy and syncope was postulated.
Catecolaminergic polymorphic ventricular tachycardia (CPVT), was an obvious consideration,
however the suppression of the ectopy during an exercise stress test, essentially
excluded this diagnosis. Brugada syndrome and arrhythmogenic right ventricular cardiomyopathy
were thought less likely as the ECG didn't show features typically associated with
these disorders. The long QT syndrome although associated with polymorphic ventricular
tachycardia, is not generally described with frequent ventricular extrasystoles at
rest or bidirectional ventricular tachycardia. This patient not only had frequent
multifocal ectopy, but had a documented episode of bi-directional ventricular tachycardia,
a feature well described in the Andersen-Tawil syndrome. The baseline ECG didn't demonstrate
the classic prominent U waves that have been documented in other ATS patients.
All the above channelopathies, besides ATS, are not traditionally reported with muscle
weakness or facial dysmorphism and given the specific documented cardiac arrhythmias
a clinical diagnosis of Andersen-Tawil syndrome was made.
In light of the lack of seizures for 5 years, the anti-epileptic medication was discontinued.
Six months later, the patient experienced recurrent syncope, without convulsive activity.
The patient described these episodes as different from those she had suffered at the
age of 18. Holter monitoring, recorded peri-event, showed non-sustained runs of bidirectional
ventricular tachycardia, as well as monomorphic ventricular tachycardia Fig. 2.
Due to accelerated symptomotology, positive ECG correlation and the clinical difference
from previous syncope, an internal cardiac defibrillator (ICD) was advised. Immediately
prior to implantation the patient became pregnant. She continued to suffer recurrent
syncope and, at the beginning of the second trimester, an ICD was implanted. A pectoral
muscle biopsy was sent for genetic analysis. This confirmed a mutation in c.652C > T
of the KCNJ2 gene, previously reported in the Andersen-Tawil syndrome [1].
After implantation the patient experienced further syncope. The internal electrogram
recorded during the episode showed no sustained arrhythmia. Witnesses described convulsive
activity and symptoms consistent with a post ictal period and the possibility of a
concurrent seizure disorder was raised. Sodium valproate was reinitiated and, to date,
there have been no further seizures.
Eight months later the patient developed recurrent polymorphic ventricular tachycardia
resulting in repeated shocks Fig. 3.
The majority of these occurred either at the onset of or during sleep, consistent
with a hypothesis generated in a previous case report [2], that autonomic instability
might precipitate haemodynamically compromising ventricular arrhythmias in patients
with Andersen-Tawil syndrome. The device was reprogrammed to allow a longer delay
before shock delivery resulting in long self terminating runs of polymorphic ventricular
tachycardia associated with pre-syncope. Carvedilol and flecainide were commenced,
and effectively suppressed ectopy but produced severe headaches requiring cessation.
Mexiletine was of no benefit. Hence due to failure of medical treatment, left stellate
ganglionectomy was performed. However, frequent ectopy and infrequent episodes of
symptomatic polymorphic ventricular tachycardia continued unabated, though fortunately
programming of the ICD has avoided recurrent shocks.
Discussion
This case report describes a 23-year old female with recurrent syncope, the Andersen-Tawil
syndrome and concomitant epilepsy. ATS is a rare genetic disorder first described
in 1971 by Dr. Ellen Andersen [3] in an 8-year old boy. Dr Rabi Tawil subsequently
clarified the underlying genetic abnormalities as well as setting out diagnostic criteria
[4]. The underlying genetic abnormality in 60% of cases relates to a missense mutation
in KCNJ2 (detected on chromosome 17q23) [5], a gene that encodes for the inward potassium
rectifier channel Kir 2.1 (IK1), leading to prolongation of the terminal phase of
the cardiac action potential. This genetic defect can result in “terminal phase” early
after depolarisations, which is thought to be demonstrated by the recurrent ventricular
ectopy as well as prominent U waves on the surface ECG [4].
The inheritance of ATS is autosomal dominant, though there is incomplete penetrance
[2]. Approximately 20% of those with a KCNJ2 mutation are asymptomatic. Conversely,
up to 40% of patients with the clinical phenotype are negative for mutations involving
KCNJ2.
The QT interval is not consistently prolonged in these patients and thus some authors
have discontinued using the previous designation of long QT 7 [6].
The diagnosis of ATS is based upon three specific features: dysmorphic abnormalities
such as hypognathia, clinodactyly, short stature, hypertelorism, low set ears, single
palmar crease and cryptochordism [7], periodic paralysis and frequent ventricular
extrasystoles [3]. A diagnosis of ATS can be made when two of the above three criteria
are met. In a patient with only one of the above additional evidence, such as an affected
family member is required [8].
No specific features of the syndrome predict the severity of arrhythmic burden or
risk of sudden cardiac death (SCD). In one study consisting of 96 patients, the incidence
of Torsades de pointes was approximately 3% [9].
Typically, periodic paralysis presents before other components of the disorder manifest
themselves. The average age of onset of muscle weakness is 5 years of age compared
to 13 years of age for cardiac arrhythmias. This may explain the difficulty in formal
diagnosis. There is no documented relation to other potassium sensitive forms of periodic
paralysis. As in this patient, weakness following prolonged exertion is common and
muscle biopsies, generally, have no specific abnormalities [10]. The underlying defect
in skeletal muscle is also due to a mutation in the IK1 channel.
The cardiac features are now thought to be due to a channelopathy that results in
varying degrees of ventricular arrhythmias [10] ranging from frequent multimorphological
ectopy to bidirectional ventricular tachycardia to polymorphic ventricular tachycardia.
Despite the impressive arrhythmic burden (up to 65% of patients in one cohort had
evidence of non-sustained ventricular tachycardia) [9]; the majority of patients with
ATS are asymptomatic [7]. Changes on the surface ECG include: prominent U waves in
the anterior leads (not associated with bradycardia or hypokalemia), increased T-U
junction and prolongation of the terminal, down sloping portion of the T wave [9].
Sudden death is rare and much less than that associated with other channelopathies
such as the Long QT or Brugada syndromes [2].
Differentiating cardiac syncope from other forms of transient loss of consciousness
can be difficult. Features more suggestive of cardiac origin include preceding feelings
of light-headedness/diaphoresis, palpitations or chest pain. They may also be associated
with activities such as prolonged standing/sitting or micturition etc. Transient loss
of consciousness associated with a seizure may demonstrate a preceding aura (visual/auditory/olfactory),
involve tongue biting, urinary incontinence, post ictal period and even focal neurological
deficits.
Convulsive syncope can be particularly difficult to discern a cause as global hypoperfusion
of the brain leads to syncope, but also associated convulsive activity.
Although it was initially felt that this patients' recurrent syncope was cardiac in
origin, the absence of a recorded arrhythmia, convulsive activity and post-ictal periods
during some of the episodes and eyewitness accounts, strongly suggested epilepsy as
an additional diagnosis. Since recommencing sodium valproate, no further seizures
have occurred. Although, an increased incidence of epilepsy is not reported in patients
with ATS and occurrence in this patient may reflect the background prevalence of epilepsy
in the general population. It could also represent the expression of her ion channelopathy
in neural tissues. Recent publications have intimated a deficit in abstract reasoning
and executive function suggesting subtle cerebral abnormalities in patients with ATS
[11]. Although it is possible that the Kir 2.1 mutation, which leads to the missense
mutation in potassium channels in cardiac myocytes, may also affect similar channels
in the brain. To the author's knowledge, it has not been proven whether this defect
results in seizures.
This case is unusual because of the significant resistance to anti-arrhythmic medication.
Only flecainide suppressed the frequency of ectopy and bidirectional ventricular tachycardia,
but could not be tolerated by the patient (The efficacy of flecainide in reducing
ectopy has been noted in other individual cases of ATS) [12], [13]. Beta-blockers
also could not be tolerated. Stellate ganglionectomy was considered even though the
episodes occurred at rest, because she was symptomatic with frequent episodes of polymorphic
ventricular tachycardia and had failed available medical treatment.
Currently there are no specific guidelines for the implantation of an ICD in patients
with Andersen-Tawil syndrome. Current consensus is that patients who are survivors
of a cardiac arrest, have recurrent syncope or sustained, symptomatic ventricular
tachyarrhythmias should be considered for ICD implantation [4].
The fetus was tested and demonstrated the same mutation as the proband, but to date
has not experienced cardiac arrhythmias, although she does have the proximal muscle
weakness and the waddling gait (currently 5 years-old).
In summary this case highlights the complexities of managing a patient with Andersen-Tawil
syndrome manifesting as refractory arrhythmia and profound proximal weakness. The
patient had concurrent epilepsy, which resulted in clinically different episodes from
those caused by the arrhythmia. The case illustrates the importance of awareness of
the clinical features of this syndrome, and in managing concomitant medical issues.
We encourage other groups to report their experience of seizures, in patients with
the ATS, to promote further research into the link between KCNJ2 mutations and neurological
disorders.