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Andersen-Tawil syndrome
International Journal of Cardiology 148 (2011) e13 – e15 www.elsevier.com/locate/ijcard
Letter to the Editor
Andersen-Tawil syndrome Robin A.P. Weir a,⁎, Colin J. Petrie a , Victoria Murday b , Iain N. Findlay a a
Department of Cardiology, Royal Alexandra Hospital, Corsebar Road, Paisley PA2 9PN, Scotland, UK b Department of Clinical Genetics, Royal Hospital for Sick Children, Glasgow, Scotland, UK Received 23 January 2009; accepted 26 January 2009 Available online 15 February 2009
Abstract Advances in the understanding of genetic aspects of cardiovascular diseases, together with an increase in the availability of genetic analysis, have resulted in not only increased diagnosis of known inherited conditions, but also the identification of novel syndromes. The combination of potassium-sensitive periodic paralysis, ventricular arrhythmias and dysmorphism, initially described by Andersen and Tawil, represents such a novel condition. We report a case in which genetic analysis led to the diagnosis of Andersen–Tawil syndrome after 15 years of protracted non-invasive and invasive investigations from initial presentation to ultimate diagnosis in a young female. In conclusion, we describe the clinical and genetic features of Andersen–Tawil syndrome and demonstrate the utility of genetic testing in the diagnosis of cardiovascular disease. © 2009 Elsevier Ireland Ltd. All rights reserved. Keywords: Andersen–Tawil syndrome; Long QT syndrome; Periodic paralysis
1. Text A 34-year-old Scottish female, resident in California, was admitted to hospital in 1990 after a syncopal event preceded by palpitations and hyperventilation. Medical history was of two bouts of limb muscle weakness in her twenties, during one of which serum potassium had been marginally low (3.2 mmol/l); a presumptive diagnosis of hypokalemic periodic paralysis had been made. Electromyography had been normal but muscle biopsy was not performed. She was on no medication. Physical examination revealed a healthy patient of short stature (1.6 m). Some minor dysmorphic features were present in her hands, which were small with short fifth fingers and bilateral clinodactyly (Fig. 1). Observations were: pulse 70 bpm regular, blood pressure 95/60 mm Hg without postural drop, oxygen saturations 100% on air and GCS 15/15. Systematic examination, including carotid sinus massage, was otherwise normal. ⁎ Corresponding author. Tel.: +44 141 211 8527; fax: +44 141 211 1791. E-mail address: [email protected] (R.A.P. Weir). 0167-5273/$ - see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2009.01.057
Blood chemistry, including creatine kinase (195 IU/l) and serum potassium (4.1 mmol/l), was normal and an electrocardiogram (ECG) revealed sinus rhythm, normal PR, QRS and QT intervals, with no ST segment abnormalities. Frequent unifocal ventricular extrasystoles were recorded on Holter monitoring. Echocardiography was normal other than minor mitral valve prolapse, with trivial regurgitation. A tilt table was undertaken; the patient became syncopal at 20 min with a mean heart rate drop from 78 to 48 bpm and a blood pressure drop from 100/60 to 59/38 mm Hg. Neurocardiogenic syncope was diagnosed and she was discharged on disopyramide and propranolol. Having returned to her native Scotland, she experienced a further episode of generalized limb weakness in 1993 that resolved after one week, during which serum potassium was within normal limits (3.9 mmol/l); she was commenced on acetazolamide 250 mg b.d. Ventricular ectopy was again apparent on ambulatory monitoring and correlated with the patient's palpitations, thus in an attempt to suppress this benign but symptomatic rhythm disturbance disopyramide and propranolol were replaced with amiodarone. Within three weeks, a routine ECG displayed prolongation of the corrected
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R.A.P. Weir et al. / International Journal of Cardiology 148 (2011) e13–e15
Fig. 1. Dysmorphic features in the hands. (A) Hands small with bilateral fifth finger clinodactyly. Some wasting of the first interosseous muscle bilaterally is apparent. (B) and (C) Superior views of fifth finger clinodactyly.
QT interval (QTc 491 ms — Fig. 2); amiodarone was therefore converted to flecainide (which did not improve her palpitations) then atenolol. Her QTc interval normalized on cessation of amiodarone (414 ms). Over the ensuing 10 years she was admitted several times with syncope preceded by palpitations, hyperventilation and chest tightness. Multiple ambulatory monitors revealed ventricular extrasystoles only. Coronary angiography was normal, and there were no inducible arrhythmias on electrophysiological studies. Anxiety with resultant hyperventilation
was felt to be a prominent feature, possibly aggravating her neurocardiogenic syncope. With developments in genetic testing, venepuncture was performed in 1997 for genetic analysis in order to investigate further the diagnosis of hypokalemic periodic paralysis. No mutations consistent with this condition were detected, but in 2005 further analysis on the original sample revealed a mutation (R218 W) in the KCNJ2 gene. A diagnosis of Andersen–Tawil syndrome was made. Andersen–Tawil syndrome, also known as long QT syndrome 7, is a rare genetic disorder characterized by the triad of potassium-sensitive periodic paralysis, ventricular arrhythmias and skeletal developmental abnormalities; around 100 cases have been reported worldwide [1]. Two forms are described: type 1, an autosomal dominant condition characterized by mutations affecting the KCNJ2 gene on chromosome 17q23.1–24.2, affects 60% while type 2, of unknown etiology, affects the remaining 40%. [2–5]. The KCNJ2 gene encodes the inward rectifier potassium channel 2 protein (Kir2.1); more than 20 mis-sense mutations (either causing loss of function or promoting dominant negative suppression of Kir2.1) have been identified to date in patients with Andersen–Tawil syndrome [2–4]. A review of ECG abnormalities in 39 patients with KCNJ2 mutations revealed variable QTc prolongation but found characteristic T–U wave patterns and enlarged U waves in the majority of affected individuals, together with frequent premature ventricular complexes compared to normal controls [5]. Bidirectional ventricular tachycardia (VT), polymorphic VT and sudden cardiac death are recognized in this condition [2,4]. In our patient, QTc prolongation was only apparent when treated with amiodarone but frequent ventricular ectopy was present throughout follow-up. A variety of physical features are recognized in the syndrome, including short stature, low-set ears, mandibular hypoplasia, hypertelorism, scoliosis and clinodactyly [1]. Proximal myopathy with normal electromyography may be evident during and between episodes of paralysis; muscle biopsy inconsistently reveals evidence of tubular aggregates within myofibrils [1]. Creatine kinase is variably elevated. Myotonia is usually absent.
Fig. 2. 12-lead ECG, recorded while patient was taking amiodarone, displaying prolongation of the QT interval (QTc 491 ms).
R.A.P. Weir et al. / International Journal of Cardiology 148 (2011) e13–e15
The diagnosis of Andersen–Tawil syndrome should be suspected in any individual who displays at least two of the characteristic triad of periodic paralysis, ECG abnormalities and dysmorphism. In addition to genetic testing (which is necessary for diagnosis of type 1), blood chemistry including serum potassium and thyroid function should be measured, ECG and Holter monitoring are mandatory, electromyography and muscle biopsy are encouraged and electrophysiological studies may be indicated if a malignant arrhythmia is suspected or documented. Although the link between Andersen–Tawil syndrome and cardiomyopathy is unclear, echocardiography is recommended. Following diagnosis, the goals of management are prevention of complications, treatment of these as they arise, and genetic counselling. Although serum potassium may be normal during and between episodes of paralysis the prevention of hypokalemia, with carbonic anhydrase inhibitors and/or daily potassium supplements, is indicated both to prevent periodic paralysis and to reduce the severity of the episodes when they occur (and additionally helps to shorten the QTc interval reducing the risk of arrhythmic complications). Imipramine has been used successfully to reduce the frequency of ventricular arrhythmias, while the combination of amiodarone and acetazolamide has been used with success in case reports of severely afflicted patients [1]. Drugs known to cause hypokalemia or to promote QTc prolongation should be avoided, while patients with evidence of syncopal polymorphic VT should be considered for implantable cardioverter defibrillators. Genetic counselling, including family screening, is mandatory. Affected individuals should undergo regular blood chemistry analysis, with annual ECG and Holter monitoring. Due to the possible association between some KCNJ2 mutations and cardiomyopathy, periodic echocardiography is recommended. A shared care approach between cardiologists, geneticists and neurologists is to be encouraged. On current therapy of oral potassium supplements and beta blockade, our
e15
patient continues to experience frequent syncope although no malignant arrhythmia has been documented to date. She has been free of periodic paralysis for over 10 years. Funding Not applicable. Conflict of Interest None of the authors have any conflict of interest to declare. Acknowledgements The authors certify that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [6]. References [1] Tawil R, Ptacek LJ, Pavlakis SG, et al. Andersen's syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. Ann Neurol 1994;35(3):326–30. [2] Tristani-Firouzi M, Jensen JL, Donaldson MR, et al. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest 2002;110(3):381–8. [3] Plaster NM, Tawil R, Tristani-Firouzi M, et al. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome. Cell 2001;105(4):511–9. [4] Donaldson MR, Jensen JL, Tristani-Firouzi M, et al. PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome. Neurology 2003;60(11):1811–6. [5] Zhang L, Benson DW, Tristani-Firouzi M, et al. Electrocardiographic features in Andersen–Tawil syndrome patients with KCNJ2 mutations: characteristic T–U-wave patterns predict the KCNJ2 genotype. Circulation 2005;111(21):2720–6. [6] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131: 149–50.
Letter to the Editor
Andersen-Tawil syndrome Robin A.P. Weir a,⁎, Colin J. Petrie a , Victoria Murday b , Iain N. Findlay a a
Department of Cardiology, Royal Alexandra Hospital, Corsebar Road, Paisley PA2 9PN, Scotland, UK b Department of Clinical Genetics, Royal Hospital for Sick Children, Glasgow, Scotland, UK Received 23 January 2009; accepted 26 January 2009 Available online 15 February 2009
Abstract Advances in the understanding of genetic aspects of cardiovascular diseases, together with an increase in the availability of genetic analysis, have resulted in not only increased diagnosis of known inherited conditions, but also the identification of novel syndromes. The combination of potassium-sensitive periodic paralysis, ventricular arrhythmias and dysmorphism, initially described by Andersen and Tawil, represents such a novel condition. We report a case in which genetic analysis led to the diagnosis of Andersen–Tawil syndrome after 15 years of protracted non-invasive and invasive investigations from initial presentation to ultimate diagnosis in a young female. In conclusion, we describe the clinical and genetic features of Andersen–Tawil syndrome and demonstrate the utility of genetic testing in the diagnosis of cardiovascular disease. © 2009 Elsevier Ireland Ltd. All rights reserved. Keywords: Andersen–Tawil syndrome; Long QT syndrome; Periodic paralysis
1. Text A 34-year-old Scottish female, resident in California, was admitted to hospital in 1990 after a syncopal event preceded by palpitations and hyperventilation. Medical history was of two bouts of limb muscle weakness in her twenties, during one of which serum potassium had been marginally low (3.2 mmol/l); a presumptive diagnosis of hypokalemic periodic paralysis had been made. Electromyography had been normal but muscle biopsy was not performed. She was on no medication. Physical examination revealed a healthy patient of short stature (1.6 m). Some minor dysmorphic features were present in her hands, which were small with short fifth fingers and bilateral clinodactyly (Fig. 1). Observations were: pulse 70 bpm regular, blood pressure 95/60 mm Hg without postural drop, oxygen saturations 100% on air and GCS 15/15. Systematic examination, including carotid sinus massage, was otherwise normal. ⁎ Corresponding author. Tel.: +44 141 211 8527; fax: +44 141 211 1791. E-mail address: [email protected] (R.A.P. Weir). 0167-5273/$ - see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2009.01.057
Blood chemistry, including creatine kinase (195 IU/l) and serum potassium (4.1 mmol/l), was normal and an electrocardiogram (ECG) revealed sinus rhythm, normal PR, QRS and QT intervals, with no ST segment abnormalities. Frequent unifocal ventricular extrasystoles were recorded on Holter monitoring. Echocardiography was normal other than minor mitral valve prolapse, with trivial regurgitation. A tilt table was undertaken; the patient became syncopal at 20 min with a mean heart rate drop from 78 to 48 bpm and a blood pressure drop from 100/60 to 59/38 mm Hg. Neurocardiogenic syncope was diagnosed and she was discharged on disopyramide and propranolol. Having returned to her native Scotland, she experienced a further episode of generalized limb weakness in 1993 that resolved after one week, during which serum potassium was within normal limits (3.9 mmol/l); she was commenced on acetazolamide 250 mg b.d. Ventricular ectopy was again apparent on ambulatory monitoring and correlated with the patient's palpitations, thus in an attempt to suppress this benign but symptomatic rhythm disturbance disopyramide and propranolol were replaced with amiodarone. Within three weeks, a routine ECG displayed prolongation of the corrected
e14
R.A.P. Weir et al. / International Journal of Cardiology 148 (2011) e13–e15
Fig. 1. Dysmorphic features in the hands. (A) Hands small with bilateral fifth finger clinodactyly. Some wasting of the first interosseous muscle bilaterally is apparent. (B) and (C) Superior views of fifth finger clinodactyly.
QT interval (QTc 491 ms — Fig. 2); amiodarone was therefore converted to flecainide (which did not improve her palpitations) then atenolol. Her QTc interval normalized on cessation of amiodarone (414 ms). Over the ensuing 10 years she was admitted several times with syncope preceded by palpitations, hyperventilation and chest tightness. Multiple ambulatory monitors revealed ventricular extrasystoles only. Coronary angiography was normal, and there were no inducible arrhythmias on electrophysiological studies. Anxiety with resultant hyperventilation
was felt to be a prominent feature, possibly aggravating her neurocardiogenic syncope. With developments in genetic testing, venepuncture was performed in 1997 for genetic analysis in order to investigate further the diagnosis of hypokalemic periodic paralysis. No mutations consistent with this condition were detected, but in 2005 further analysis on the original sample revealed a mutation (R218 W) in the KCNJ2 gene. A diagnosis of Andersen–Tawil syndrome was made. Andersen–Tawil syndrome, also known as long QT syndrome 7, is a rare genetic disorder characterized by the triad of potassium-sensitive periodic paralysis, ventricular arrhythmias and skeletal developmental abnormalities; around 100 cases have been reported worldwide [1]. Two forms are described: type 1, an autosomal dominant condition characterized by mutations affecting the KCNJ2 gene on chromosome 17q23.1–24.2, affects 60% while type 2, of unknown etiology, affects the remaining 40%. [2–5]. The KCNJ2 gene encodes the inward rectifier potassium channel 2 protein (Kir2.1); more than 20 mis-sense mutations (either causing loss of function or promoting dominant negative suppression of Kir2.1) have been identified to date in patients with Andersen–Tawil syndrome [2–4]. A review of ECG abnormalities in 39 patients with KCNJ2 mutations revealed variable QTc prolongation but found characteristic T–U wave patterns and enlarged U waves in the majority of affected individuals, together with frequent premature ventricular complexes compared to normal controls [5]. Bidirectional ventricular tachycardia (VT), polymorphic VT and sudden cardiac death are recognized in this condition [2,4]. In our patient, QTc prolongation was only apparent when treated with amiodarone but frequent ventricular ectopy was present throughout follow-up. A variety of physical features are recognized in the syndrome, including short stature, low-set ears, mandibular hypoplasia, hypertelorism, scoliosis and clinodactyly [1]. Proximal myopathy with normal electromyography may be evident during and between episodes of paralysis; muscle biopsy inconsistently reveals evidence of tubular aggregates within myofibrils [1]. Creatine kinase is variably elevated. Myotonia is usually absent.
Fig. 2. 12-lead ECG, recorded while patient was taking amiodarone, displaying prolongation of the QT interval (QTc 491 ms).
R.A.P. Weir et al. / International Journal of Cardiology 148 (2011) e13–e15
The diagnosis of Andersen–Tawil syndrome should be suspected in any individual who displays at least two of the characteristic triad of periodic paralysis, ECG abnormalities and dysmorphism. In addition to genetic testing (which is necessary for diagnosis of type 1), blood chemistry including serum potassium and thyroid function should be measured, ECG and Holter monitoring are mandatory, electromyography and muscle biopsy are encouraged and electrophysiological studies may be indicated if a malignant arrhythmia is suspected or documented. Although the link between Andersen–Tawil syndrome and cardiomyopathy is unclear, echocardiography is recommended. Following diagnosis, the goals of management are prevention of complications, treatment of these as they arise, and genetic counselling. Although serum potassium may be normal during and between episodes of paralysis the prevention of hypokalemia, with carbonic anhydrase inhibitors and/or daily potassium supplements, is indicated both to prevent periodic paralysis and to reduce the severity of the episodes when they occur (and additionally helps to shorten the QTc interval reducing the risk of arrhythmic complications). Imipramine has been used successfully to reduce the frequency of ventricular arrhythmias, while the combination of amiodarone and acetazolamide has been used with success in case reports of severely afflicted patients [1]. Drugs known to cause hypokalemia or to promote QTc prolongation should be avoided, while patients with evidence of syncopal polymorphic VT should be considered for implantable cardioverter defibrillators. Genetic counselling, including family screening, is mandatory. Affected individuals should undergo regular blood chemistry analysis, with annual ECG and Holter monitoring. Due to the possible association between some KCNJ2 mutations and cardiomyopathy, periodic echocardiography is recommended. A shared care approach between cardiologists, geneticists and neurologists is to be encouraged. On current therapy of oral potassium supplements and beta blockade, our
e15
patient continues to experience frequent syncope although no malignant arrhythmia has been documented to date. She has been free of periodic paralysis for over 10 years. Funding Not applicable. Conflict of Interest None of the authors have any conflict of interest to declare. Acknowledgements The authors certify that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [6]. References [1] Tawil R, Ptacek LJ, Pavlakis SG, et al. Andersen's syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. Ann Neurol 1994;35(3):326–30. [2] Tristani-Firouzi M, Jensen JL, Donaldson MR, et al. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest 2002;110(3):381–8. [3] Plaster NM, Tawil R, Tristani-Firouzi M, et al. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome. Cell 2001;105(4):511–9. [4] Donaldson MR, Jensen JL, Tristani-Firouzi M, et al. PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome. Neurology 2003;60(11):1811–6. [5] Zhang L, Benson DW, Tristani-Firouzi M, et al. Electrocardiographic features in Andersen–Tawil syndrome patients with KCNJ2 mutations: characteristic T–U-wave patterns predict the KCNJ2 genotype. Circulation 2005;111(21):2720–6. [6] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131: 149–50.