- Email: [email protected]
Type 2 short QT syndrome and vestibular dysfunction: Mirror of the Jervell and Lange-Nielsen syndrome?
Letters to the Editor
291
[32] Tulino V, Cacace C, Tulino D, Imbalzano E, Dattilo G. Clinical variants in Ebstein's anomaly, Int J Cardiol 168 (5). Oct 2013;12:4969–70. [33] Zhang DY, Lozier J, Chang R, et al. Case study and review: treatment of tricuspid prosthetic valve thrombosis. Int J Cardiol Dec 15 2012;162(1):14–9. [34] Denardo SJ, Davis KE, Tcheng JE. Effectiveness and safety of reduced-dose enoxaparin in non-ST-segment elevation acute coronary syndrome followed by antiplatelet therapy alone for percutaneous coronary intervention. Am J Cardiol Nov 1 2007;100(9):1376–82. [35] Patanè S, Marte F, Sturiale M, Dattilo G. ST-segment elevation and diminution of prostate-specific antigen in a patient with coronary spasm and without significant coronary stenoses. Int J Cardiol Apr 14 2011;148(2):e31–3. [36] Reed GW, Cannon CP. Triple oral antithrombotic therapy in atrial fibrillation and coronary artery stenting. Clin Cardiol Sep 2013;36(10):585–94. [37] Arboix A, García-Eroles L, Massons JB, Oliveres M, Pujades R, Targa C. Atrial fibrillation and stroke: clinical presentation of cardioembolic versus atherothrombotic infarction. Int J Cardiol Mar 31 2000;73(1):33–42. [38] Guo Y, Pisters R, Apostolakis S, et al. Guo Y, Pisters R, Apostolakis S. Stroke risk and suboptimal thromboprophylaxis in Chinese patients with atrial fibrillation: would the novel oral anticoagulants have an impact? Int J Cardiol Sep 2013;168(1):515–22.
Fig. 2. CT image showing the presence of a large area of cortical–subcortical hypodense in the distribution of the right middle cerebral.
[31] Dattilo G, Lamari A, Tulino V, et al. Congenital valvular heart disease with high familial penetrance. Recenti Prog Med Dec 2012;103(12):581–3.
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.11.079
Type 2 short QT syndrome and vestibular dysfunction: Mirror of the Jervell and LangeNielsen syndrome? Alice Maltret a,⁎, Sylvette Wiener-Vacher b, Charlotte Denis c, Fabrice Extramiana d, Marie Paule Morisseau-Durand e, Veronique Fressart f, Damien Bonnet a, Christian Chabbert g a
Department of Pediatric Cardiology, Hospital Necker, AP-HP, Paris, France Department of Vestibulometry, Hospital Robert Debré, AP-HP, Paris, France Department of Pediatric Cardiology, Château des Côtes, Les loges en Josas, France d University Paris Diderot, Hospital Bichat, AP-HP, Paris, France e Department of Oto-Rhino-Laryngology, Hospital Necker, AP-HP, Paris, France f Department of Biochemistry, Hospital Pitie-Salpetriere, AP-HP, Paris, France g INSERM U1051, Institute for Neurosciences of Montpellier, France b c
a r t i c l e
i n f o
Article history: Received 30 August 2013 Accepted 25 November 2013 Available online 4 December 2013 Keywords: Short QT syndrome Inner ear Imbalance Canalar dysfunction Pediatric KCNQ1
In cardiac myocytes the role of potassium is central for resting membrane potential as well as for the action potential course [1,2]. ⁎ Corresponding author. Tel.: +33 1 44 49 43 42; fax: +33 1 44 49 43 40. E-mail address: [email protected] (A. Maltret).
Accordingly mutations in KCNQ1 resulting in a loss of function in IKs are associated with ventricular repolarization prolongation leading to ventricular arrhythmias (long QT syndromes) and also with congenital bilateral deafness in its homozygous presentation (Jervell and Lange-Nielsen syndrome) [3,4]. Mutations leading to a gain of function in KCNQ1 gene have also been described and are associated with the type 2 short QT syndrome (SQTS) characterized by ventricular repolarization shortening and life threatening ventricular arrhythmias [5]. We here report a case of inner ear dysfunction in a patient with type 2 short QT syndrome. The baby girl was born preterm at 32 weeks by cesarean section that was prompted by fetal bradycardia. The postnatal basal twelvelead surface electrocardiogram (ECG) (Fig. 1) showed a slow sinus rhythm (HR = 69 bpm) with an extremely short QT interval duration (QT = 260 ms, QTc Bazett = 279 ms, QTc Fridericia = 272 ms). The ECG-Holter monitoring has repeatedly recorded both slow sinus and junctional rhythms (24-hour mean heart rate at 50 bpm)
292
Letters to the Editor
Fig. 1. Electrocardiogram at birth.
without supra-ventricular or ventricular arrhythmias. Since repolarization has been described as shortening less in type 1 SQTS when the heart beat increases in comparison with healthy subjects [6], we temporary paced the heart through the esophagus, but it showed no effect on repolarization duration. A genetic analysis was performed by direct sequencing after amplification of the coding region of KCNQ1. We found the previously described V141M mutation in KCNQ1 [7]. Regarding parents and siblings, clinical and ECG assessment were normal. A slight delay in motor skill acquisition was observed and initially presumed to be a consequence of the premature birth. She was able to sit without support at 12 months (adjusted age). Some oscillation of the upper body and head were observed, and
ground positions were naturally reached to play. She walked unassisted at an adjusted age of 22 months. Some months after walk acquisition, many falls were observed particularly on irregular or unsteady floor. No ataxia was observed; nevertheless spontaneous left nystalgmus was registered (9 eye saccades/30 s). Afterwards, a complete balance testing concluded to a profound alteration of the canalar function. CT scan showed no anatomical abnormalities of the semi-circular canals. To date, both the macular functions and hearing seems normal. We introduced hydroquinidine medication at 18 months old (25 up to 40 mg/kg per day, in order to maintain therapeutic levels of 1–2 mcg/ml). No significant difference was observed on the ECG during the first 2 years of treatment. Then, a new ECG profile could
Fig. 2. Electrocardiogram under hydroquinidine medication.
Letters to the Editor
be observed, which shows a junctional escape rhythm (HR = 53 bpm) and a prolongation of the QT interval duration (QT = 340 ms, QTc Bazett =318 ms, QTc Fridericia = 325 ms) (Fig. 2). Hydroquinidine is well tolerated and has not been interrupted ever since. We trained the family members and school staff to resuscitation maneuvers and an automated external defibrillator was made available both at home and school. No cardiac event has occurred after 4 and a half years of follow-up. To the best of our knowledge this case is the first report of altered canalar function without hearing deficiency in a patient with type 2 short QT syndrome. The V141M mutation has been expressed and is associated with a gain in function in IKs leading to action potential duration shortening [7] which is the basis of type 2 SQTS. Management of such patient is challenging. Since the patient was very young at diagnosis and no cardiac event occurred during the first 18 months of follow-up, non-invasive clinical issues were favored. Invasive cardiac electrophysiology study was not proposed to the family. Hydroquinidine treatment was introduced and after 2 years of treatment a modified ECG was eventually observed with a much higher dosage than usually proposed in pediatric patient. In the absence of strong evidence, one can only elaborate on the functional consequences of the gain-of-function in KCNQ1 on the endolymph ionic homeostasis. Strict maintenance of K+ concentration into the inner ear endolymph is mandatory to hearing and balance function [8]. In case of gain-of-function mutations, IKs channel is constitutively open. This situation might not be critical in the stria vascularis (secretory zone of the cochlea) where marginal cells display K+ concentration similar to those of the endolymph, and in which the intrastrial space continuously provides strong electrical gradient allowing K+ accumulation from the perilymph. Conversely, constitutive opening of IKs channel may have severe functional consequences in the vestibule and especially in the semicircular canals cristas that solely rely on the K+ secretion by the surrounding dark cells that do not possess such electrical barrier to generate positive potential [9]. In this specific secretory zone, the V141M mutation on KCNQ1 may prevent its action as a “valve” replenishing K+ into the endolymph compartment when required. However, further clinical observations as well as experimental studies are needed to support such hypothesis.
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.11.078
293
A fortuitous association of SQTS and vestibular malfunction from another cause cannot be ruled out, especially considering the ototoxic effect of quinine derivatives [10], even if hypoacusis and dizziness due to quinidine drugs are mostly observed in case of excessive dose. Our patient had moreover her first symptoms of imbalance before introduction of the hydroquinidine. So far, no vestibular dysfunction has been reported in the few identified cases of type 2 SQTS. However, balance trouble may be of difficult diagnosis in infants and toddlers as imbalance symptoms are usually mild because canalar defects are usually progressively counterbalanced by vision and proprioception senses during growth. Nevertheless, our observation supports the need for systematic inner ear testing in type 2 SQTS patients. The authors are grateful to Dr D Marcus and Mrs S Pierre for helpful comments.
References [1] Honoré E, Attali B, Romey G, et al. Cloning, expression, pharmacology and regulation of a delayed-rectifier K + channel in mouse heart. EMBO J 1991;10:2805–11. [2] Sakagami M, Fukazawa K, Matsunaga T, et al. Cellular localization of rat IsK protein in the stria vascularis by immunohistochemical observation. Hear Res 1991;56:168–72. [3] Neyroud N, Tesson F, Denjoy I, et al. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange Nielsen cardioauditory syndrome. Nat Genet 1997;15:186–9. [4] Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the Q–T interval and sudden death. Am Heart J 1957;54:59–68. [5] Chen YH, Xu SJ, Bendahhou S, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science 2003;299:251–4. [6] Wolpert C, Schimpf R, Giustetto C, et al. Further insights into the effect of quinidine in short QT syndrome caused by a mutation in HERG. J Cardiovasc Electrophysiol 2005;6:54–8. [7] Hong K, Piper DR, Diaz-Valdecantos A, et al. De novo KCNQ1 mutation responsible for atrial fibrillation and short QT syndrome in utero. Cardiovasc Res 2005;68:433–40. [8] Hibino H, Kirachi Y. Molecular and physiological bases of the K+ circulation in the mammalian inner ear. Physiology 2006;21:336–45. [9] Marcus DC, Shen Z. Slowly activating voltage-dependent K + conductance is apical pathway for K+ secretion in vestibular dark cells. Am J Physiol 1994;267(36):857–64. [10] Shine NP, Coates H. Systemic ototoxicity: a review. East Afr Med J Oct 2005;82(10):536–9.
291
[32] Tulino V, Cacace C, Tulino D, Imbalzano E, Dattilo G. Clinical variants in Ebstein's anomaly, Int J Cardiol 168 (5). Oct 2013;12:4969–70. [33] Zhang DY, Lozier J, Chang R, et al. Case study and review: treatment of tricuspid prosthetic valve thrombosis. Int J Cardiol Dec 15 2012;162(1):14–9. [34] Denardo SJ, Davis KE, Tcheng JE. Effectiveness and safety of reduced-dose enoxaparin in non-ST-segment elevation acute coronary syndrome followed by antiplatelet therapy alone for percutaneous coronary intervention. Am J Cardiol Nov 1 2007;100(9):1376–82. [35] Patanè S, Marte F, Sturiale M, Dattilo G. ST-segment elevation and diminution of prostate-specific antigen in a patient with coronary spasm and without significant coronary stenoses. Int J Cardiol Apr 14 2011;148(2):e31–3. [36] Reed GW, Cannon CP. Triple oral antithrombotic therapy in atrial fibrillation and coronary artery stenting. Clin Cardiol Sep 2013;36(10):585–94. [37] Arboix A, García-Eroles L, Massons JB, Oliveres M, Pujades R, Targa C. Atrial fibrillation and stroke: clinical presentation of cardioembolic versus atherothrombotic infarction. Int J Cardiol Mar 31 2000;73(1):33–42. [38] Guo Y, Pisters R, Apostolakis S, et al. Guo Y, Pisters R, Apostolakis S. Stroke risk and suboptimal thromboprophylaxis in Chinese patients with atrial fibrillation: would the novel oral anticoagulants have an impact? Int J Cardiol Sep 2013;168(1):515–22.
Fig. 2. CT image showing the presence of a large area of cortical–subcortical hypodense in the distribution of the right middle cerebral.
[31] Dattilo G, Lamari A, Tulino V, et al. Congenital valvular heart disease with high familial penetrance. Recenti Prog Med Dec 2012;103(12):581–3.
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.11.079
Type 2 short QT syndrome and vestibular dysfunction: Mirror of the Jervell and LangeNielsen syndrome? Alice Maltret a,⁎, Sylvette Wiener-Vacher b, Charlotte Denis c, Fabrice Extramiana d, Marie Paule Morisseau-Durand e, Veronique Fressart f, Damien Bonnet a, Christian Chabbert g a
Department of Pediatric Cardiology, Hospital Necker, AP-HP, Paris, France Department of Vestibulometry, Hospital Robert Debré, AP-HP, Paris, France Department of Pediatric Cardiology, Château des Côtes, Les loges en Josas, France d University Paris Diderot, Hospital Bichat, AP-HP, Paris, France e Department of Oto-Rhino-Laryngology, Hospital Necker, AP-HP, Paris, France f Department of Biochemistry, Hospital Pitie-Salpetriere, AP-HP, Paris, France g INSERM U1051, Institute for Neurosciences of Montpellier, France b c
a r t i c l e
i n f o
Article history: Received 30 August 2013 Accepted 25 November 2013 Available online 4 December 2013 Keywords: Short QT syndrome Inner ear Imbalance Canalar dysfunction Pediatric KCNQ1
In cardiac myocytes the role of potassium is central for resting membrane potential as well as for the action potential course [1,2]. ⁎ Corresponding author. Tel.: +33 1 44 49 43 42; fax: +33 1 44 49 43 40. E-mail address: [email protected] (A. Maltret).
Accordingly mutations in KCNQ1 resulting in a loss of function in IKs are associated with ventricular repolarization prolongation leading to ventricular arrhythmias (long QT syndromes) and also with congenital bilateral deafness in its homozygous presentation (Jervell and Lange-Nielsen syndrome) [3,4]. Mutations leading to a gain of function in KCNQ1 gene have also been described and are associated with the type 2 short QT syndrome (SQTS) characterized by ventricular repolarization shortening and life threatening ventricular arrhythmias [5]. We here report a case of inner ear dysfunction in a patient with type 2 short QT syndrome. The baby girl was born preterm at 32 weeks by cesarean section that was prompted by fetal bradycardia. The postnatal basal twelvelead surface electrocardiogram (ECG) (Fig. 1) showed a slow sinus rhythm (HR = 69 bpm) with an extremely short QT interval duration (QT = 260 ms, QTc Bazett = 279 ms, QTc Fridericia = 272 ms). The ECG-Holter monitoring has repeatedly recorded both slow sinus and junctional rhythms (24-hour mean heart rate at 50 bpm)
292
Letters to the Editor
Fig. 1. Electrocardiogram at birth.
without supra-ventricular or ventricular arrhythmias. Since repolarization has been described as shortening less in type 1 SQTS when the heart beat increases in comparison with healthy subjects [6], we temporary paced the heart through the esophagus, but it showed no effect on repolarization duration. A genetic analysis was performed by direct sequencing after amplification of the coding region of KCNQ1. We found the previously described V141M mutation in KCNQ1 [7]. Regarding parents and siblings, clinical and ECG assessment were normal. A slight delay in motor skill acquisition was observed and initially presumed to be a consequence of the premature birth. She was able to sit without support at 12 months (adjusted age). Some oscillation of the upper body and head were observed, and
ground positions were naturally reached to play. She walked unassisted at an adjusted age of 22 months. Some months after walk acquisition, many falls were observed particularly on irregular or unsteady floor. No ataxia was observed; nevertheless spontaneous left nystalgmus was registered (9 eye saccades/30 s). Afterwards, a complete balance testing concluded to a profound alteration of the canalar function. CT scan showed no anatomical abnormalities of the semi-circular canals. To date, both the macular functions and hearing seems normal. We introduced hydroquinidine medication at 18 months old (25 up to 40 mg/kg per day, in order to maintain therapeutic levels of 1–2 mcg/ml). No significant difference was observed on the ECG during the first 2 years of treatment. Then, a new ECG profile could
Fig. 2. Electrocardiogram under hydroquinidine medication.
Letters to the Editor
be observed, which shows a junctional escape rhythm (HR = 53 bpm) and a prolongation of the QT interval duration (QT = 340 ms, QTc Bazett =318 ms, QTc Fridericia = 325 ms) (Fig. 2). Hydroquinidine is well tolerated and has not been interrupted ever since. We trained the family members and school staff to resuscitation maneuvers and an automated external defibrillator was made available both at home and school. No cardiac event has occurred after 4 and a half years of follow-up. To the best of our knowledge this case is the first report of altered canalar function without hearing deficiency in a patient with type 2 short QT syndrome. The V141M mutation has been expressed and is associated with a gain in function in IKs leading to action potential duration shortening [7] which is the basis of type 2 SQTS. Management of such patient is challenging. Since the patient was very young at diagnosis and no cardiac event occurred during the first 18 months of follow-up, non-invasive clinical issues were favored. Invasive cardiac electrophysiology study was not proposed to the family. Hydroquinidine treatment was introduced and after 2 years of treatment a modified ECG was eventually observed with a much higher dosage than usually proposed in pediatric patient. In the absence of strong evidence, one can only elaborate on the functional consequences of the gain-of-function in KCNQ1 on the endolymph ionic homeostasis. Strict maintenance of K+ concentration into the inner ear endolymph is mandatory to hearing and balance function [8]. In case of gain-of-function mutations, IKs channel is constitutively open. This situation might not be critical in the stria vascularis (secretory zone of the cochlea) where marginal cells display K+ concentration similar to those of the endolymph, and in which the intrastrial space continuously provides strong electrical gradient allowing K+ accumulation from the perilymph. Conversely, constitutive opening of IKs channel may have severe functional consequences in the vestibule and especially in the semicircular canals cristas that solely rely on the K+ secretion by the surrounding dark cells that do not possess such electrical barrier to generate positive potential [9]. In this specific secretory zone, the V141M mutation on KCNQ1 may prevent its action as a “valve” replenishing K+ into the endolymph compartment when required. However, further clinical observations as well as experimental studies are needed to support such hypothesis.
0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.11.078
293
A fortuitous association of SQTS and vestibular malfunction from another cause cannot be ruled out, especially considering the ototoxic effect of quinine derivatives [10], even if hypoacusis and dizziness due to quinidine drugs are mostly observed in case of excessive dose. Our patient had moreover her first symptoms of imbalance before introduction of the hydroquinidine. So far, no vestibular dysfunction has been reported in the few identified cases of type 2 SQTS. However, balance trouble may be of difficult diagnosis in infants and toddlers as imbalance symptoms are usually mild because canalar defects are usually progressively counterbalanced by vision and proprioception senses during growth. Nevertheless, our observation supports the need for systematic inner ear testing in type 2 SQTS patients. The authors are grateful to Dr D Marcus and Mrs S Pierre for helpful comments.
References [1] Honoré E, Attali B, Romey G, et al. Cloning, expression, pharmacology and regulation of a delayed-rectifier K + channel in mouse heart. EMBO J 1991;10:2805–11. [2] Sakagami M, Fukazawa K, Matsunaga T, et al. Cellular localization of rat IsK protein in the stria vascularis by immunohistochemical observation. Hear Res 1991;56:168–72. [3] Neyroud N, Tesson F, Denjoy I, et al. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange Nielsen cardioauditory syndrome. Nat Genet 1997;15:186–9. [4] Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the Q–T interval and sudden death. Am Heart J 1957;54:59–68. [5] Chen YH, Xu SJ, Bendahhou S, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science 2003;299:251–4. [6] Wolpert C, Schimpf R, Giustetto C, et al. Further insights into the effect of quinidine in short QT syndrome caused by a mutation in HERG. J Cardiovasc Electrophysiol 2005;6:54–8. [7] Hong K, Piper DR, Diaz-Valdecantos A, et al. De novo KCNQ1 mutation responsible for atrial fibrillation and short QT syndrome in utero. Cardiovasc Res 2005;68:433–40. [8] Hibino H, Kirachi Y. Molecular and physiological bases of the K+ circulation in the mammalian inner ear. Physiology 2006;21:336–45. [9] Marcus DC, Shen Z. Slowly activating voltage-dependent K + conductance is apical pathway for K+ secretion in vestibular dark cells. Am J Physiol 1994;267(36):857–64. [10] Shine NP, Coates H. Systemic ototoxicity: a review. East Afr Med J Oct 2005;82(10):536–9.