Article Text
Abstract
‘Ion channelopathies’ have emerged in the past decade as a new cause of several neurological diseases. These Mendelian disorders are caused by mutations in genes that encode ion channel subunits and are often characterised by paroxysmal attacks of brain or muscle dysfunction, interspersed with periods of clinical normality. Andersen–Tawil syndrome is one of the rarest and is characterised clinically by the triad of periodic paralysis, cardiac dysrhythmias and skeletal abnormalities. Mutations in a potassium channel gene, KCNJ2 which encodes the potassium channel, Kir2.1, underlie the disorder. Here, the authors describe a patient and review the clinical spectrum and genetic features of the disorder.
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The story
A 51-year-old woman had presented at the age of 9 years with attacks of muscle weakness affecting all four limbs, typically lasting from hours to days. Precipitants for the attacks, which occurred about once a month, included moderate exercise and prolonged rest of several days. Muscle function was normal between attacks. She had no muscle pain or stiffness. In addition, she also complained of palpitations lasting seconds but occurring up to four times a week, possibly triggered by stress. There were no other cardiac symptoms. The patient's two younger brothers were similarly affected. Her mother had experienced palpitations and died following a cardiac arrest at the age of 38 years (it is not known if she had also experienced attacks of muscle weakness). Our patient's motor weakness initially led to the diagnosis of cerebral palsy by paediatricians. Subsequently, her attacks of muscle weakness were dismissed as psychological in origin.
Examination at the age of 51 years revealed short stature (132 cm). She had micromelia (small hands and feet) with clinodactyly of her hands and syndactyly of her toes. Her ears were low set and there was clear mandibular hypoplasia (figure 1). She also had bilateral ptosis and mild bilateral facial weakness. Examination of her limb muscles revealed normal bulk, slight reduction in power (MRC grade 4+) and normal reflexes. Sensory examination was normal. Cardiac examination was unremarkable.
Her attacks of muscle weakness pointed to a form of periodic paralysis. Routine electromyography was normal but the long exercise test using the McManis protocol demonstrated a clear reduction in both compound muscle action potential (CMAP) and area under the CMAP curve consistent with periodic paralysis (figure 2) (the hypothenar muscle is exercised for 5 min for periods of 15 s with 5 s of rest in between; following this, the CMAP is measured at 2 min intervals for up to 50 min). Her resting 12 lead ECG was normal, as were her serum electrolytes, including potassium level taken during an attack.
Although mutations in the CACNA1S (encodes the skeletal muscle calcium channel, CaV1.1) and SCN4A (encodes the skeletal muscle sodium channel, NaV1.4) genes account for most cases of primary periodic paralyses, the additional cardiac and dysmorphic features raised the possibility of Andersen–Tawil syndrome (ATS). Sequencing of her KCNJ2 gene identified an arginine to tryptophan substitution at amino acid position 218 (R218W) which confirmed the diagnosis. This mutation was also present in her two affected brothers but not in a panel of over 200 control chromosomes.
Discussion
Neurological ion ‘channelopathies’ are generally divided into those which affect the brain (eg, episodic ataxias, familial hyperekplexia and various epilepsy syndromes such as generalised epilepsy with febrile seizures and severe myoclonic epilepsy of infancy) and those whose primary target is skeletal muscle (eg, hyper/hypokalaemic periodic paralysis, myotonia congenita). ATS is unique in the sense that it is a multisystem channelopathy. Although its triad of cardinal features is periodic paralysis, ventricular dysrhythmias and distinct physical characteristics,1 valvular heart disease, hypoplastic kidney and cognitive impairment have also been reported.2 It is extremely rare (prevalence of approximately 1/1 000 000) and is often overlooked as a cause of both periodic paralysis and the long QT syndrome. It is inherited in an autosomal dominant fashion although sporadic cases are common. The variability in expression can lead to delay in diagnosis as some individuals may have only cardiac manifestations and in others the characteristic physical features may be too subtle to be recognised. Unfortunately, failure to recognise it can lead to delay in treatment, particularly of cardiac dysrhythmias which can occasionally be fatal.
Skeletal muscle features
Episodic attacks of muscle weakness is the primary manifestation in most patients. The primary periodic paralyses are traditionally classified as hyper- or hypokalaemic depending on the serum potassium level during an attack although in some cases there may not be a marked change (so-called normokalaemic).3 Mutations in SCN4A, which encodes the voltage gated skeletal muscle NaV1.4, underlie hyperkalaemic periodic paralysis, which is allelic with paramyotonia congenita and potassium aggravated myotonia. Mutations in the calcium channel gene CACNA1S account for most cases of hypokalaemic periodic paralysis, the most common form of periodic paralysis (table). In ATS most patients have hypokalaemic episodes but potassium levels may be raised or normal during an attack.
Hyperkalaemic periodic paralysis | Hypokalaemic periodic paralysis | Andersen–Tawil syndrome | |
---|---|---|---|
Occurrence | <1:100,000 | ∼ 1:100,000 | ∼1:1,000,000 |
Age of onset (years) | <10 | <20 | <20 |
Duration of attacks | Hours | Hours to days | Hours to days |
Triggers for attacks | Rest after exercise; ↑ potassium intake | Rest after exercise, carbohydrate meal | Rest after exercise, carbohydrate meal |
Cardiac features | No | No | Yes |
Dysmorphic features | No | No | Yes |
Additional feature | Myopathy | Myopathy | Cognitive impairment? |
K+ level during attack | ↑ | ↓ | ↓ Usually but also ↔ or ↑ |
EMG | Myotonia (some cases). Long exercise test: ↑ CMAP initially and then ↓ | Long exercise test: ↓ CMAP | Long exercise test: ↓ CMAP |
Causative gene | SCN4A | CACNA1S (60–80%) | KCNJ2 |
SCN4A | |||
Gene expression | Skeletal muscle | Skeletal muscle | Skeletal and cardiac muscle |
Treatment of periodic paralysis | Acetazolamide | Acetazolamide, potassium supplements | Acetazolamide, potassium supplements |
CMAP, compound muscle action potential; EMG, electromyography.
Precipitants for paralysis, which generally lasts from hours to days and rarely weeks, include rest after exercise, prolonged rest and carbohydrate rich meals. Potassium ingestion can help in attack resolution. Attack frequency and severity generally abate with age. In between episodes of paralysis, muscle strength is normal although a fixed myopathy may develop in later years.
Cardiac features
The co-occurrence of ATS and a long QT interval in one of the earliest descriptions of the syndrome pointed to a common ion channel defect as the likely cause. A combination of linkage studies and a candidate gene approach excluded several long QT loci and finally established mutations in KCNJ2 as the cause. There is a broad spectrum of cardiac abnormalities,4 with bidirectional ventricular tachycardia and bigeminy the most common arrhythmias. Polymorphic ventricular tachycardia and rarely non-fatal cardiac arrest have also been described. In addition to a long QT interval, common ECG findings include ventricular ectopy and a large ‘U’ wave reflecting impaired cardiac muscle repolarisation (figure 3). In some patients, a cardiac phenotype may be the sole manifestation. In our case, the proband's mother died following a cardiac arrest at the age of 38 years, suggesting that she too may have had the syndrome.
Dysmorphic features
The most common skeletal features include mandibular hypoplasia, hypotelorism, low set ears, clinodactyly, syndactyly of the toes, small hands and small feet. Microcephaly and a high arched palate have also been described. However, as with the cardiac and muscle manifestations, there is phenotypic heterogeneity, with some patients having only very subtle physical signs.
Genetic features
Missense mutations and in a few cases small deletions in KCNJ2 underlie the syndrome in approximately 70% of patients, with locus heterogeneity likely to account for the remainder. The KCNJ2 gene encodes the inwardly rectifying potassium channel Kir2.1.5 The channel exists as a dimer, each of which contains two transmembrane segments (M1 and M2) connected by an extracellular interlinker that also forms the channel pore (figure 4). It is widely expressed in brain, skeletal and cardiac muscle. The normal function of this channel is to stabilise the resting membrane potential of the cell and shape the terminal portion of the action potential.
Most Andersen–Tawil mutations that have been functionally studied result in a reduction in potassium current and hence loss of Kir2.1 channel function.4 6 Because it is an autosomal dominant disorder, affected patients will have a combination of normal and mutant Kir2.1 channels. The mutant channels suppress the activity and function of normal channels by exerting a dominant negative effect. Dysfunction of the Kir2.1 channel in skeletal and cardiac muscle affects the electrical properties of the cell membrane leading to attacks of paralysis and cardiac dysrhythmias. The mechanisms underlying the dysmorphic features however are not understood.
Diagnosis
ATS should be considered in any patient who presents with periodic paralysis, and indeed in patients with a long QT, especially in view of the considerable clinical heterogeneity of the phenotype. It is the presence of cardiac and dysmorphic features in addition to the paralytic attacks that is the clue to the diagnosis and hence these should always be looked for in patients with periodic paralysis. Once secondary causes of periodic paralysis are excluded (eg, thyroid disorders), ideally the potassium level early in an attack should be measured. Electromyography is important because ATS patients have a positive long exercise test (as observed by a decrement in the CMAP amplitude of >40% from baseline) according to the McManis protocol, which confirms the presence of aberrations in skeletal muscle membrane excitability. However, the test cannot distinguish hypokalaemic periodic paralysis from ATS. It is the identification of mutations in KCNJ2 that confirms the diagnosis of the syndrome.
Practice Points
ATS is characterised by the triad of periodic paralysis, cardiac dysrhythmias and dysmorphic features.
It should be considered in the differential diagnosis of both periodic paralysis and the long QT syndrome.
Clinical neurophysiological testing using the long exercise test protocol demonstrates a reduction in CMAP amplitude.
Mutations in the KCNJ2 gene account for approximately 70% of cases.
Cardiac evaluation is important as ventricular dysrhythmias resulting in fatal cardiac arrest have been reported.
The carbonic anhydrase inhibitors are effective treatment for the periodic paralysis.
Treatment
Treatment is aimed at reducing the frequency and severity of paralytic attacks and preventing the development of malignant ventricular dysrhythmias. For attacks of muscle weakness, the pharmacological mainstays are the carbonic anhydrase inhibitors, acetazolamide and dichlorphenamide. Their mechanisms of action are uncertain but both are effective as they are in the other types of periodic paralysis. Oral potassium supplementation to maintain an elevated potassium level may also prevent paralytic attacks and importantly prevent lengthening of the QT interval. In addition, patients should avoid any known triggers of their attacks.
Although life threatening cardiac dysrhythmias are the most feared consequence of the syndrome, in practice these are rare compared with other long QT syndrome. Current evidence indicates that maintaining a short QTc interval to prevent degeneration into torsade de pointes may be achieved with β-adrenergic blockade, usually propanolol. This should be coupled with avoiding drugs, particularly other cardiac agents, which lengthen the QT interval. If this fails or for high risk individuals, other measures such as insertion of a pacemaker or defibrillator may be needed.
Acknowledgments
MGH is supported by an MRC Centre grant (G0601943). SR is a Wellcome Clinical Research Training Fellow. Further information about the UK service for diagnosis of muscle channelopathies supported by the National Commissioning Group (NCG) is available from MGH (m.hanna@ion.ucl.ac.uk).
Footnotes
Patient consent Obtained.
Competing interests None.
Provenance and peer review Not commissioned; not externally peer reviewed.
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