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Jervell and Lange-Nielsen syndrome: neurologic and cardiologic evaluation
Jervell and Lange-Nielsen Syndrome: Neurologic and Cardiologic Evaluation Atilla Ilhan, MD*, Cemal Tuncer, MD†, Sezer S. Komsuoglu, MD‡, and Sinem Kali, MD* Recurrent syncope, malignant ventricular arrhythmias, and sudden death are complications of the long QT syndrome (LQTS). Two well-known syndromes with long QT intervals are known. The Jervell and Lange-Nielsen syndrome (JLNS) is characterized by prolongation of the QT interval, deafness, and autosomal-recessive inheritance, and the Romano-Ward syndrome is characterized by a prolonged QT interval, autosomal-dominant inheritance, and no deafness. In the present study assessment was performed of the diagnostic importance of the ventricular derepolarization parameters, clinical features, and prevalence of JLNS among 132 children with congenital hearing loss (CHL). In the CHL group the mean QT, QTc, JT, and JTc intervals and the dispersion values (QT-d, JT-d, QTc-d, and JTc-d) were significantly longer than those of control subjects (n ⴝ 96) (P < 0.05). Patients with CHL and JLNS (n ⴝ 5) had significantly longer mean values of QT, QTc, JT, and JTc intervals and dispersion values than those of CHL without JLNS (n ⴝ 127) and control subjects (P < 0.05). The results suggest that assessment of ventricular derepolarization parameters in children with CHL will be helpful in the early detection of JLNS because infants with CHL cannot accurately describe the symptoms of syncope. © 1999 by Elsevier Science Inc. All rights reserved.
Romano-Ward form of the LQTS is characterized by an autosomal-dominant inheritance without familial deafness. The second form of the disorder, called the Jervell and Lange-Nielsen syndrome (JLNS), has an autosomal-recessive pattern of inheritance and is associated with deafness [1-4]. The purpose of this study was to elucidate the importance of cardiac screening for the presence of LQTS among children with congenital hearing loss (CHL). The authors also describe the prevalence of patients with JLNS in this group. Patients and Methods
The long QT syndrome (LQTS) is an infrequently inherited disorder characterized by a prolonged QT interval on the electrocardiogram, sudden death from ventricular arrhythmias, and recurrent syncope. There are two well-known syndromes with a long QT interval. The
Patient Population. This study was established at the Malatya DeafMute School in Turkey. Children with acquired deafness were excluded from the study by otologic examination and history (n ⫽ 17). One hundred thirty-two children with CHL were enrolled in this study (50 females and 82 males; mean age ⫽ 13 ⫾ 3 years, range ⫽ 6-17 years). Family pedigrees were constructed, and attempts were made to enroll all living immediate family members (siblings, parents, aunts, uncles, and grandparents) of all children with LQTS in the study and to identify any affected family members who had died. In the control group the authors evaluated 96 children (42 females and 54 males; mean age ⫽ 14 ⫾ 3 years, range ⫽ 5-17 years). Children with CHL and control subjects were matched for sex, age, height, and weight. Identification of LQTS. Twelve-lead electrocardiograms with a paper speed of 50 mm/second and standardization of 2 mV were obtained from all children with CHL and control subjects. Attempts were also made to obtain 12-lead electrocardiograms of all living family members of children with LQTS. The study electrocardiograms were interpreted by two physicians unaware of the clinical findings, and all R-R, QT, and JT intervals were measured in all leads. All parameters were calculated at least twice for all subjects. The QTc and JTc intervals were calculated by Bazett’s formula, which adjust the QT and JT intervals for the heart rate [5]. QT and JT intervals were measured from the beginning and from the end of the QRS complex to the end of T wave, respectively. The authors did not include u waves in the measurement. The diagnosis of LQTS was made according to the new diagnostic criteria of Schwartz et al. [6]. Repolarization dispersion parameters (QT-d, JT-d, QTc-d, and JTc-d) were calculated as the difference in millimeters (1 mm ⫽ 20 ms) between the maximal and minimal values of QT, JT, QTc, and JTc in the standard leads. Patients receiving medication known to prolong the QT interval
From the Departments of *Neurology and †Cardiology; Inonu University Medical Faculty; Turgut Ozal Medical Center; Malatya; and ‡Department of Neurology; Kocaeli University Medical Faculty; Kocaeli, Turkey.
Communications should be addressed to: Dr. Ilhan; Department of Neurology; Inonu University Medical Faculty; Malatya 44069, Turkey. Received March 10, 1999; accepted July 15, 1999.
Ilhan A, Tuncer C, Komsuoglu SS, Kali S. Jervell and Lange-Nielsen syndrome: Neurologic and cardiologic evaluation. Pediatr Neurol 1999;21:809-813.
Introduction
© 1999 by Elsevier Science Inc. All rights reserved. PII S0887-8994(99)00100-9 ● 0887-8994/99/$20.00
Ilhan et al: Jervell and Lange-Nielsen Syndrome 809
Table 1.
Electrocardiographic, echocardiographic, and radiologic abnormalities in subjects with congenital hearing loss Electrocardiographic Abnormalities
n
QT prolongation Borderline (440-460 ms) Absolute (⬎ 460 ms) Total T wave inversion Complete RBBB Incomplete RBBB Low atrial rhythm First degree atrioventricular rhythm Complete RBBB plus L anterior hemiblock
1 4 5 1 3 8 1 1 1
Echocardiographic Abnormalities
n
Interatrial aneurysm Atrial septal defect Mitral valve prolapse Innocent murmur
1 1 8 4
Radiologic Abnormalities
n
Mondini’s deformity Partial or total bone labyrinth obliteration Bilateral or unilateral large vestibular aqueduct
1 13 11
Abbreviations: L ⫽ Left R ⫽ Right bundle branch block
(such as antiarrhythmic agents) or who had valvular heart disease, pericardial or myocardial disease, congenital heart disease, or rhythm and conduction disorders were excluded from the study. Children with CHL were divided into two subgroups. In Group 1 were children with CHL and long QT intervals (i.e., patients with JLNS). In Group 2 were children with CHL but without long QT intervals. All laboratory evaluations, including biochemical and hematologic parameters, electroencephalograms, and neurologic examinations, were within normal limits in children with CHL and control subjects. Two-dimensional and M-mode echocardiography and cranial computed tomography were performed in children with CHL and affected family members. Statistical Analysis. The mean values of ventricular derepolarization parameters between the CHL group and control subjects were evaluated for statistically significant differences using the independent sample t test. Subgroups were compared with the control group by the KruskalWallis one way analysis of variance and the Mann-Whitney U test. Values are presented as the mean ⫾ 1 S.D.
Results The electrocardiographic, echocardiographic, and radiologic abnormalities in the CHL group are presented in Table 1. In the CHL group the mean QT, QTc, JT, and JTc intervals were significantly longer than those of control subjects. Also, the dispersion values (QT-d, JT-d, QTc-d, and JTc-d) of the CHL group were significantly longer than those of control subjects (Table 2). Two of the children with CHL (1.51%) had one or more family members with a QTc interval greater than 440 ms, and three of the children with CHL (2.27%) had a family history of syncope or death before 50 years of age. The enrolled family members consisted of 48 (two with a QTc interval greater than 440 ms [affected], 46 with a QTc interval of 440 ms [unaffected]), and one without a recorded electrocardiogram (family member was dead). Five of the children with CHL (3.78%) had JLNS (Group 1). Among them, only two had signs of JLNS (syncope and seizure), but they had not received any medication. Two of the patients were relatives (siblings) (Fig 1). The child with syncope had longer R-R, QT, and QTc durations than the other four children with JLNS (R-R ⫽ 960 ms vs 620 ms, 600 ms, 600 ms, and 740 ms; QT ⫽ 560 ms
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vs 450 ms, 400 ms, 400 ms, and 400 ms; and QTc ⫽ 572 ms vs 570 ms, 516 ms, 516 ms, and 465 ms) (Fig 2). When asked to describe the seizure characteristics in detail, his father said “he becomes unconscious first and lies limp like a dead body for several seconds before he starts convulsing, after that he falls down, his eyes go up into his head, and his whole body jerks.” Patients in Group 1 (JLNS; n ⫽ 5) had significantly longer mean values of QT, QTc, JT, and JTc intervals than those of Group 2 (CHL only; n ⫽ 127) and control subjects (n ⫽ 96) (QT ⫽ 418 ⫾ 70 ms vs 344 ⫾ 23 ms and vs 325 ⫾ 11 ms; QTc ⫽ 500 ⫾ 38 ms vs 408 ⫾ 22 ms and vs 383 ⫾ 26 ms; JT ⫽ 302 ⫾ 65 ms vs 249 ⫾ 34 ms and vs 228 ⫾ 36 ms; and JTc ⫽ 389 ⫾ 36 ms vs 291 ⫾ 28 ms and 269 ⫾ 26 ms, respectively; P ⬍ 0.05). Also, the mean values of the QT, QTc, JT, and JTc intervals in Group 2 were longer than those of control subjects (P ⬍ 0.05). The indexes of dispersion of repolarization (QT-d, JT-d, QTc-d, and JTc-d) were significantly longer in Group 1 Table 2. Comparison of ventricular derepolarization parameters in children with congenital hearing loss and normal subjects
Age (yr) RR (ms) QT (ms) QTc (ms) JT (ms) JTc (ms) QT-d (ms) QTc-d (ms) JT-d (ms) JTc-d (ms)
CHL Group (n ⴝ 132)
Normal Group (n ⴝ 96)
P Value
13 ⫾ 3 (6-17) 717 ⫾ 119 (440-990) 348 ⫾ 32 (276-560) 414 ⫾ 42 (319-572) 253 ⫾ 31 (183-368) 301 ⫾ 31 (246-473) 49 ⫾ 16 (20-90) 46 ⫾ 12 (30-95) 51 ⫾ 21 (10-100) 48 ⫾ 19 (20-90)
14 ⫾ 3 (5-17) 730 ⫾ 90 (590-940) 325 ⫾ 11 (306-350) 383 ⫾ 26 (328-430) 228 ⫾ 36 (205-380) 269 ⫾ 26 (223-402) 33 ⫾ 13 (10-70) 33 ⫾ 14 (10-70) 28 ⫾ 16 (10-80) 27 ⫾ 14 (10-80)
NS NS ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.01 ⬍0.001 ⬍0.02 ⬍0.001 ⬍0.003
Data presented as mean ⫾ S.D., with the range in parentheses. Abbreviations: CHL ⫽ Congenital hearing loss NS ⫽ Not significant
Figure 1. Pedigree of three patients in Group 1. The QTc interval, which is greater than 440 ms, is given below each symbol. Circle ⫽ female; square ⫽ male; solid squares ⫽ affected person; Sy ⫽ syncopal attacks; Se ⫽ seizure; MMR ⫽ motor-mental retardation; N ⫽ no signs; square with slash ⫽ affected family member who died.
than in Group 2 or control subjects (QT-d ⫽ 63 ⫾ 10 ms vs 49 ⫾ 16 ms and vs 33 ⫾ 13 ms; JT-d ⫽ 73 ⫾ 8 ms vs 43 ⫾ 11 ms and vs 33 ⫾ 14 ms; QTc-d ⫽ 60 ⫾ 8 ms vs
48 ⫾ 21 ms and vs 28 ⫾ 16 ms; and JTc-d ⫽ 62 ⫾ 11 ms vs 45 ⫾ 18 ms and vs 27 ⫾ 14 ms, respectively; P ⬍ 0.05). Also, all index values of dispersion in Group 2 were
Figure 2. The dispersion values of subgroup subjects and controls. Single asterisks indicate significant difference between Group 1 and Group 2 and between Group 1 and control subjects (P ⬍0.05). Double asterisks indicate significant difference between Group 2 and control subjects (P ⬍0.05).
Ilhan et al: Jervell and Lange-Nielsen Syndrome 811
significantly longer than those of control subjects (P ⬍ 0.05) (Fig 2).
Discussion Syncope or seizures occurring during childhood is one of the most problematic issues for pediatric neurologists. Because infants and young children cannot describe the symptoms of their attacks accurately, physicians generally have to take the history from the parents. With the JLNS form of the LQTS, which is characterized by syncope, seizures, and sudden death caused by polymorphic ventricular tachycardia (torsades de pointes) in children with congenital deafness, obtaining a detailed history is more difficult. Some pediatric neurologists recommend performing an electrocardiogram on all children presenting with seizures. Because the LQTS is an uncommon inherited disease and routine performance of electrocardiography is not practical, the authors believe it will be more cost-effective to perform electrocardiographic screening only for children with CHL. The diagnosis of the LQTS also presents difficulty in some situations. In cases of borderline QT prolongation and an unremarkable family history the definitive diagnosis may be more difficult. Also, because the QT interval is inherently variable in relation to heart rate, autonomic tone, age, medication use, and the presence of other disorders, recording only one QTc value greater than 0.44 ms is not sufficient for the diagnosis of LQTS, and repeated QTc calculations are needed [7]. Unless electrocardiographic data are interpreted in the light of the clinical information, diagnostic errors can still be made. Therefore the authors used repeated QTc calculations and other diagnostic criteria as defined by Schwartz et al. [6] for the diagnosis of LQTS. Because preliminary data suggest that the QT intervals in patients with this syndrome fail to shorten appropriately compared with those of control subjects, exercise testing may be useful in the diagnosis of LQTS [8]. Previous studies have evaluated the usefulness of QT interval dispersion in patients with long QT intervals as a risk predictor for sudden death caused by ventricular arrhythmias, such as torsades de pointes and ventricular fibrillation. QT dispersion represents variations in repolarization in different regions of the myocardium, and increased dispersion of ventricular recovery time may provide the substrate for ventricular tachyarrhythmias [9-12]. Experimental and clinical electrophysiologic studies have suggested that inhomogeneous myocardial repolarization may lead to lethal re-entrant ventricular arrhythmia [13, 14]. In the present study the authors also confirmed the presence of an increased dispersion repolarization in patients affected by the LQTS. Because the JT interval truly represents ventricular repolarization, the authors included JT interval parameters, including JT, JTc, JT-d, and JTc-d, in addition to the QT interval parameters. The
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results of the related parameters were parallel to that of the QT interval parameters (Table 2 and Fig 2). JLNS is a rare disease that affects less than 1% of all deaf children. In published reports the prevalence ranges between 0% and 0.43% (average ⫽ 0.21%) [15-18]. However, the authors determined the prevalence of JLNS to be 3.78% (five cases among 132 children with CHL). The authors believe that the high JLNS prevalence in their study may be because consanguineous marriage is common in the authors’ population. Also, subjects with CHL generally prefer to seek their marriage partners among the population with CHL, and thus the probability of JLNS may be increased. The syncopal attacks are frequently misinterpreted as a seizure disorder, and antiepileptic drugs may be inappropriately prescribed to patients with LQTS who present with seizure if the true diagnosis is not established. In some patients the frequency of seizure may decrease or cease with these drugs. Antiepileptic agents are thought to increase the seizure threshold but not to affect the other ischemic symptoms [19]. In the authors’ study, two of the children with CHL (2.27%) had syncope/seizure attacks in their histories but had not received any antiepileptic medication. Because seizures caused by cardiogenic disorders generally begin with unconsciousness, the authors believe that the physician taking the patient’s history should ask whether the patient becomes unconscious before the onset of seizures. The association between deafness and QT prolongation in the JLNS is not clear. Neyround et al. [20] described a disease gene of the JLNS, KVLQT1 (LQTS linked to chromosome 11), which has a critical role not only in ventricular repolarization but also in the control of endolymph homeostasis, which is essential for normal hearing function. Mutations in the KVLQT1 gene can lead to borderline QT prolongation compatible with the RomanoWard phenotype in the heterozygous state and to JLNS with deafness and a severe cardiac phenotype in the homozygous state. Genetic heterogeneity has been identified in the LQTS. In 1991, Keating et al. [21] reported that the LQTS phenotype was linked with a marker on chromosome 11 (at 11p15.5). The marker on chromosome 11 is related to the gene encoding the ras oncogene that, in turn, has been implicated in sympathetic receptor-effector coupling and ion channel modulation. However, this potential linkage of gene and disease does not always have meaning in the pathogenetic sense because the chromosome of this ion channel is primarily atrial in its distribution. Also, a number of families with the LQTS have been reported to have disease not linked to 11p15.5 [22-24]. Recently, two additional types of genes were identified, including HERG (a potassium channel gene) for LQT2 (LQTS linked to chromosome 7) and SCNA5A (a sodium channel gene) for LQT3 (LQTS linked to chromosome 3) [25-27]. The fourth locus for LQT4 has been mapped to chromosome 4 (4q25-27), but the mutant gene has not yet been identified
[20]. It has been demonstrated that IsK, an apparent potassium channel subunit encoded by the KCNE1 gene (the possible gene for LQT5) on chromosome 21, regulates both KVLQT1 and HERG. It is clear that the Romano-Ward syndrome (with at least five different loci) and the JLNS (with at least two different loci; KVLQT1 and KCNE1) are genetically heterogenous [17,24-28]. The most frequent form of the LQTS is the RomanoWard syndrome; the JLNS is a rarer but more malignant variant. Beta-adrenergic blocking drugs serve as the foundation for treatment in symptomatic patients with a history of syncope or aborted cardiac arrest and in some asymptomatic LQTS patients who are members of high-risk families. Left cervicothoracic stellate ganglionectomy has been used effectively in high-risk patients with recurrent syncope uncontrolled by beta-blocking agents and pacemakers. The transvenous implantable cardioverter defibrillator devices have been used effectively in selected highrisk patients with disease refractory to more conventional forms of therapy [29,30]. The children with JLNS in this study were treated with a beta-blocking drug for 8 months. The authors did not observe any cardiac problems, and the QT intervals were shortened with treatment. Whenever a child with CHL presents with attacks of unconsciousness that precede seizures responsive to antiepileptic drugs but the attacks of unconsciousness continue and the family history includes sudden unexplained deaths, the LQTS is a strong possible cause, and cardiac screening should be carefully performed. References [1] Romano C, Gemme G, Pongiglione R. Aritmie cardiache rare dell’eta’pediatrica. Clin Pediatr (Bologna) 1963;45:656-83. [2] Ward OC. A new familial cardiac syndrome in children. J Irish Med Assoc 1964;54:103-6. [3] Jervell A, Lang-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the QT interval and sudden death. Am Heart J 1957;54:59-68. [4] Cusimano F, Martines E, Rizzo C. Jervell and Lang-Nielsen syndrome. Int J Pediatr Otorhinolaryngol 1991;22:49-58. [5] Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920;7:353-70. [6] Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation 1993;88: 782-4. [7] Vincent MG, Timothy WK, Leppert M, Keating M. The spectrum of symptoms and QT intervals in carriers of the gene for the long QT syndrome. N Engl J Med 1992;327:846-52. [8] Schwartz PJ, Pereti M, Malliani A. The long QT syndrome. Am Heart J 1975;89:378-90. [9] Day CP, McComb JM, Campbell RWF. QT dispersion: An indication of arrhythmia risk in patients with long QT intervals. Br Heart J 1990;63:342-4.
[10] Barr CS, Naas A, Freeman M, Lang CC, Struthers AD. QT dispersion and sudden death in heart failure. Lancet 1994;343:327-9. [11] Perkiomaki JS, Koistinen J, Yli-Mayry S, Huikuri HV. Dispersion of QT interval in patients with and without susceptibility to ventricular tachyarrhythmias after previous myocardial infarction. J Am Coll Cardiol 1995;267:174-9. [12] Merx W, Yoon MS, Han J. The role of local disparity in conduction and recovery time or ventricular vulnerability to fibrillation. Am Heart J 1977;94:603-10. [13] Kuo CS, Reddy CP, Munakata K, Surawicz B. Mechanism of ventricular arrhythmias caused by increased dispersion of repolarization. Eur Heart J 1985;6 (Suppl D):63-70. [14] Vassallo JA, Cassidy DM, Kindwall KE, Marchlinski FE, Josephson ME. Nonuniform recovery of excitability in the left ventricle. Circulation 1988;78:1365-72. [15] Fraser GR, Froggat P, Murphy T. Genetics aspects of the cardioauditory syndrome of Jervell and Lange-Nielsen (congenital deafness and electrocardiographic abnormalities). Ann Hum Genet 1964;28: 133-57. [16] Hashiba K. Hereditary QT prolongation syndrome in Japan: Genetic analysis and pathologic findings of the conducting system. Jpn Circ J 1978;42:1133-9. [17] Duggal P, Vesely MR, Wattanasirichaigoon D, Villafane J, Kaushik V. Mutation of the gene for IsK associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long QT syndrome. Circulation 1998;97:142-6. [18] Komsuoglu B, Goldeli O, Kulan K, et al. The Jervell and Lange-Nielsen syndrome. Int J Cardiol 1994;47:189-92. [19] Balbir S, Saad AS, Moh’d AH, Saleh MD, Nabil B. Idiopathic long QT syndrome: Asking the right question. Lancet 1993;341:741-2. [20] Neyround N, Tesson F, Denjoy I. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen syndrome. Nat Genet 1997;15:186-9. [21] Keating M, Atkinson D, Dunn C, Timothy K, Vincent GM, Leppert M. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science 1991;252:704-6. [22] Curran ME, Atkinson D, Timothy K, et al. Locus heterogeneity of dominant long QT syndrome. J Clin Invest 1993;92:799-803. [23] Dean JC, Cross S, Jennings K. Evidence of genetic and phenotypic heterogeneity in the Romano-Ward syndrome. J Med Genet 1993;30:947-50. [24] Akimoto K, Matsuoka R, Kasanuki H, et al. Linkage analysis in a Japanese long QT syndrome family. Kokyuto Junkan 1993;41:463-5. [25] Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995;80:795-803. [26] Wang Q, Curran ME, Splawski I, et al. Positional cloning of the novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 1996;12:17-23. [27] Wang Q, Shen J, Splawski I, et al. SCNA5 mutations associated with inherited cardiac arrhythmia, long QT syndrome. Cell 1995;80:805-11. [28] Schott J, Charpentier F, Peltier S, et al. Mapping of a gene for long QT syndrome to chromosome 4q25-27. Am J Hum Genet 1995;57: 1114-22. [29] Schwartz PJ, Locati E, Moss AJ. Left cardiac sympathetic denervation in the therapy of the congenital long QT syndrome: A worldwide report. Circulation 1991;84:503-11. [30] Ouriel K, Moss AJ. Long QT syndrome: An indication for cervicothoracic sympathectomy. Cardiovasc Surg 1995;3:475-8.
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Romano-Ward form of the LQTS is characterized by an autosomal-dominant inheritance without familial deafness. The second form of the disorder, called the Jervell and Lange-Nielsen syndrome (JLNS), has an autosomal-recessive pattern of inheritance and is associated with deafness [1-4]. The purpose of this study was to elucidate the importance of cardiac screening for the presence of LQTS among children with congenital hearing loss (CHL). The authors also describe the prevalence of patients with JLNS in this group. Patients and Methods
The long QT syndrome (LQTS) is an infrequently inherited disorder characterized by a prolonged QT interval on the electrocardiogram, sudden death from ventricular arrhythmias, and recurrent syncope. There are two well-known syndromes with a long QT interval. The
Patient Population. This study was established at the Malatya DeafMute School in Turkey. Children with acquired deafness were excluded from the study by otologic examination and history (n ⫽ 17). One hundred thirty-two children with CHL were enrolled in this study (50 females and 82 males; mean age ⫽ 13 ⫾ 3 years, range ⫽ 6-17 years). Family pedigrees were constructed, and attempts were made to enroll all living immediate family members (siblings, parents, aunts, uncles, and grandparents) of all children with LQTS in the study and to identify any affected family members who had died. In the control group the authors evaluated 96 children (42 females and 54 males; mean age ⫽ 14 ⫾ 3 years, range ⫽ 5-17 years). Children with CHL and control subjects were matched for sex, age, height, and weight. Identification of LQTS. Twelve-lead electrocardiograms with a paper speed of 50 mm/second and standardization of 2 mV were obtained from all children with CHL and control subjects. Attempts were also made to obtain 12-lead electrocardiograms of all living family members of children with LQTS. The study electrocardiograms were interpreted by two physicians unaware of the clinical findings, and all R-R, QT, and JT intervals were measured in all leads. All parameters were calculated at least twice for all subjects. The QTc and JTc intervals were calculated by Bazett’s formula, which adjust the QT and JT intervals for the heart rate [5]. QT and JT intervals were measured from the beginning and from the end of the QRS complex to the end of T wave, respectively. The authors did not include u waves in the measurement. The diagnosis of LQTS was made according to the new diagnostic criteria of Schwartz et al. [6]. Repolarization dispersion parameters (QT-d, JT-d, QTc-d, and JTc-d) were calculated as the difference in millimeters (1 mm ⫽ 20 ms) between the maximal and minimal values of QT, JT, QTc, and JTc in the standard leads. Patients receiving medication known to prolong the QT interval
From the Departments of *Neurology and †Cardiology; Inonu University Medical Faculty; Turgut Ozal Medical Center; Malatya; and ‡Department of Neurology; Kocaeli University Medical Faculty; Kocaeli, Turkey.
Communications should be addressed to: Dr. Ilhan; Department of Neurology; Inonu University Medical Faculty; Malatya 44069, Turkey. Received March 10, 1999; accepted July 15, 1999.
Ilhan A, Tuncer C, Komsuoglu SS, Kali S. Jervell and Lange-Nielsen syndrome: Neurologic and cardiologic evaluation. Pediatr Neurol 1999;21:809-813.
Introduction
© 1999 by Elsevier Science Inc. All rights reserved. PII S0887-8994(99)00100-9 ● 0887-8994/99/$20.00
Ilhan et al: Jervell and Lange-Nielsen Syndrome 809
Table 1.
Electrocardiographic, echocardiographic, and radiologic abnormalities in subjects with congenital hearing loss Electrocardiographic Abnormalities
n
QT prolongation Borderline (440-460 ms) Absolute (⬎ 460 ms) Total T wave inversion Complete RBBB Incomplete RBBB Low atrial rhythm First degree atrioventricular rhythm Complete RBBB plus L anterior hemiblock
1 4 5 1 3 8 1 1 1
Echocardiographic Abnormalities
n
Interatrial aneurysm Atrial septal defect Mitral valve prolapse Innocent murmur
1 1 8 4
Radiologic Abnormalities
n
Mondini’s deformity Partial or total bone labyrinth obliteration Bilateral or unilateral large vestibular aqueduct
1 13 11
Abbreviations: L ⫽ Left R ⫽ Right bundle branch block
(such as antiarrhythmic agents) or who had valvular heart disease, pericardial or myocardial disease, congenital heart disease, or rhythm and conduction disorders were excluded from the study. Children with CHL were divided into two subgroups. In Group 1 were children with CHL and long QT intervals (i.e., patients with JLNS). In Group 2 were children with CHL but without long QT intervals. All laboratory evaluations, including biochemical and hematologic parameters, electroencephalograms, and neurologic examinations, were within normal limits in children with CHL and control subjects. Two-dimensional and M-mode echocardiography and cranial computed tomography were performed in children with CHL and affected family members. Statistical Analysis. The mean values of ventricular derepolarization parameters between the CHL group and control subjects were evaluated for statistically significant differences using the independent sample t test. Subgroups were compared with the control group by the KruskalWallis one way analysis of variance and the Mann-Whitney U test. Values are presented as the mean ⫾ 1 S.D.
Results The electrocardiographic, echocardiographic, and radiologic abnormalities in the CHL group are presented in Table 1. In the CHL group the mean QT, QTc, JT, and JTc intervals were significantly longer than those of control subjects. Also, the dispersion values (QT-d, JT-d, QTc-d, and JTc-d) of the CHL group were significantly longer than those of control subjects (Table 2). Two of the children with CHL (1.51%) had one or more family members with a QTc interval greater than 440 ms, and three of the children with CHL (2.27%) had a family history of syncope or death before 50 years of age. The enrolled family members consisted of 48 (two with a QTc interval greater than 440 ms [affected], 46 with a QTc interval of 440 ms [unaffected]), and one without a recorded electrocardiogram (family member was dead). Five of the children with CHL (3.78%) had JLNS (Group 1). Among them, only two had signs of JLNS (syncope and seizure), but they had not received any medication. Two of the patients were relatives (siblings) (Fig 1). The child with syncope had longer R-R, QT, and QTc durations than the other four children with JLNS (R-R ⫽ 960 ms vs 620 ms, 600 ms, 600 ms, and 740 ms; QT ⫽ 560 ms
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vs 450 ms, 400 ms, 400 ms, and 400 ms; and QTc ⫽ 572 ms vs 570 ms, 516 ms, 516 ms, and 465 ms) (Fig 2). When asked to describe the seizure characteristics in detail, his father said “he becomes unconscious first and lies limp like a dead body for several seconds before he starts convulsing, after that he falls down, his eyes go up into his head, and his whole body jerks.” Patients in Group 1 (JLNS; n ⫽ 5) had significantly longer mean values of QT, QTc, JT, and JTc intervals than those of Group 2 (CHL only; n ⫽ 127) and control subjects (n ⫽ 96) (QT ⫽ 418 ⫾ 70 ms vs 344 ⫾ 23 ms and vs 325 ⫾ 11 ms; QTc ⫽ 500 ⫾ 38 ms vs 408 ⫾ 22 ms and vs 383 ⫾ 26 ms; JT ⫽ 302 ⫾ 65 ms vs 249 ⫾ 34 ms and vs 228 ⫾ 36 ms; and JTc ⫽ 389 ⫾ 36 ms vs 291 ⫾ 28 ms and 269 ⫾ 26 ms, respectively; P ⬍ 0.05). Also, the mean values of the QT, QTc, JT, and JTc intervals in Group 2 were longer than those of control subjects (P ⬍ 0.05). The indexes of dispersion of repolarization (QT-d, JT-d, QTc-d, and JTc-d) were significantly longer in Group 1 Table 2. Comparison of ventricular derepolarization parameters in children with congenital hearing loss and normal subjects
Age (yr) RR (ms) QT (ms) QTc (ms) JT (ms) JTc (ms) QT-d (ms) QTc-d (ms) JT-d (ms) JTc-d (ms)
CHL Group (n ⴝ 132)
Normal Group (n ⴝ 96)
P Value
13 ⫾ 3 (6-17) 717 ⫾ 119 (440-990) 348 ⫾ 32 (276-560) 414 ⫾ 42 (319-572) 253 ⫾ 31 (183-368) 301 ⫾ 31 (246-473) 49 ⫾ 16 (20-90) 46 ⫾ 12 (30-95) 51 ⫾ 21 (10-100) 48 ⫾ 19 (20-90)
14 ⫾ 3 (5-17) 730 ⫾ 90 (590-940) 325 ⫾ 11 (306-350) 383 ⫾ 26 (328-430) 228 ⫾ 36 (205-380) 269 ⫾ 26 (223-402) 33 ⫾ 13 (10-70) 33 ⫾ 14 (10-70) 28 ⫾ 16 (10-80) 27 ⫾ 14 (10-80)
NS NS ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.01 ⬍0.001 ⬍0.02 ⬍0.001 ⬍0.003
Data presented as mean ⫾ S.D., with the range in parentheses. Abbreviations: CHL ⫽ Congenital hearing loss NS ⫽ Not significant
Figure 1. Pedigree of three patients in Group 1. The QTc interval, which is greater than 440 ms, is given below each symbol. Circle ⫽ female; square ⫽ male; solid squares ⫽ affected person; Sy ⫽ syncopal attacks; Se ⫽ seizure; MMR ⫽ motor-mental retardation; N ⫽ no signs; square with slash ⫽ affected family member who died.
than in Group 2 or control subjects (QT-d ⫽ 63 ⫾ 10 ms vs 49 ⫾ 16 ms and vs 33 ⫾ 13 ms; JT-d ⫽ 73 ⫾ 8 ms vs 43 ⫾ 11 ms and vs 33 ⫾ 14 ms; QTc-d ⫽ 60 ⫾ 8 ms vs
48 ⫾ 21 ms and vs 28 ⫾ 16 ms; and JTc-d ⫽ 62 ⫾ 11 ms vs 45 ⫾ 18 ms and vs 27 ⫾ 14 ms, respectively; P ⬍ 0.05). Also, all index values of dispersion in Group 2 were
Figure 2. The dispersion values of subgroup subjects and controls. Single asterisks indicate significant difference between Group 1 and Group 2 and between Group 1 and control subjects (P ⬍0.05). Double asterisks indicate significant difference between Group 2 and control subjects (P ⬍0.05).
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significantly longer than those of control subjects (P ⬍ 0.05) (Fig 2).
Discussion Syncope or seizures occurring during childhood is one of the most problematic issues for pediatric neurologists. Because infants and young children cannot describe the symptoms of their attacks accurately, physicians generally have to take the history from the parents. With the JLNS form of the LQTS, which is characterized by syncope, seizures, and sudden death caused by polymorphic ventricular tachycardia (torsades de pointes) in children with congenital deafness, obtaining a detailed history is more difficult. Some pediatric neurologists recommend performing an electrocardiogram on all children presenting with seizures. Because the LQTS is an uncommon inherited disease and routine performance of electrocardiography is not practical, the authors believe it will be more cost-effective to perform electrocardiographic screening only for children with CHL. The diagnosis of the LQTS also presents difficulty in some situations. In cases of borderline QT prolongation and an unremarkable family history the definitive diagnosis may be more difficult. Also, because the QT interval is inherently variable in relation to heart rate, autonomic tone, age, medication use, and the presence of other disorders, recording only one QTc value greater than 0.44 ms is not sufficient for the diagnosis of LQTS, and repeated QTc calculations are needed [7]. Unless electrocardiographic data are interpreted in the light of the clinical information, diagnostic errors can still be made. Therefore the authors used repeated QTc calculations and other diagnostic criteria as defined by Schwartz et al. [6] for the diagnosis of LQTS. Because preliminary data suggest that the QT intervals in patients with this syndrome fail to shorten appropriately compared with those of control subjects, exercise testing may be useful in the diagnosis of LQTS [8]. Previous studies have evaluated the usefulness of QT interval dispersion in patients with long QT intervals as a risk predictor for sudden death caused by ventricular arrhythmias, such as torsades de pointes and ventricular fibrillation. QT dispersion represents variations in repolarization in different regions of the myocardium, and increased dispersion of ventricular recovery time may provide the substrate for ventricular tachyarrhythmias [9-12]. Experimental and clinical electrophysiologic studies have suggested that inhomogeneous myocardial repolarization may lead to lethal re-entrant ventricular arrhythmia [13, 14]. In the present study the authors also confirmed the presence of an increased dispersion repolarization in patients affected by the LQTS. Because the JT interval truly represents ventricular repolarization, the authors included JT interval parameters, including JT, JTc, JT-d, and JTc-d, in addition to the QT interval parameters. The
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results of the related parameters were parallel to that of the QT interval parameters (Table 2 and Fig 2). JLNS is a rare disease that affects less than 1% of all deaf children. In published reports the prevalence ranges between 0% and 0.43% (average ⫽ 0.21%) [15-18]. However, the authors determined the prevalence of JLNS to be 3.78% (five cases among 132 children with CHL). The authors believe that the high JLNS prevalence in their study may be because consanguineous marriage is common in the authors’ population. Also, subjects with CHL generally prefer to seek their marriage partners among the population with CHL, and thus the probability of JLNS may be increased. The syncopal attacks are frequently misinterpreted as a seizure disorder, and antiepileptic drugs may be inappropriately prescribed to patients with LQTS who present with seizure if the true diagnosis is not established. In some patients the frequency of seizure may decrease or cease with these drugs. Antiepileptic agents are thought to increase the seizure threshold but not to affect the other ischemic symptoms [19]. In the authors’ study, two of the children with CHL (2.27%) had syncope/seizure attacks in their histories but had not received any antiepileptic medication. Because seizures caused by cardiogenic disorders generally begin with unconsciousness, the authors believe that the physician taking the patient’s history should ask whether the patient becomes unconscious before the onset of seizures. The association between deafness and QT prolongation in the JLNS is not clear. Neyround et al. [20] described a disease gene of the JLNS, KVLQT1 (LQTS linked to chromosome 11), which has a critical role not only in ventricular repolarization but also in the control of endolymph homeostasis, which is essential for normal hearing function. Mutations in the KVLQT1 gene can lead to borderline QT prolongation compatible with the RomanoWard phenotype in the heterozygous state and to JLNS with deafness and a severe cardiac phenotype in the homozygous state. Genetic heterogeneity has been identified in the LQTS. In 1991, Keating et al. [21] reported that the LQTS phenotype was linked with a marker on chromosome 11 (at 11p15.5). The marker on chromosome 11 is related to the gene encoding the ras oncogene that, in turn, has been implicated in sympathetic receptor-effector coupling and ion channel modulation. However, this potential linkage of gene and disease does not always have meaning in the pathogenetic sense because the chromosome of this ion channel is primarily atrial in its distribution. Also, a number of families with the LQTS have been reported to have disease not linked to 11p15.5 [22-24]. Recently, two additional types of genes were identified, including HERG (a potassium channel gene) for LQT2 (LQTS linked to chromosome 7) and SCNA5A (a sodium channel gene) for LQT3 (LQTS linked to chromosome 3) [25-27]. The fourth locus for LQT4 has been mapped to chromosome 4 (4q25-27), but the mutant gene has not yet been identified
[20]. It has been demonstrated that IsK, an apparent potassium channel subunit encoded by the KCNE1 gene (the possible gene for LQT5) on chromosome 21, regulates both KVLQT1 and HERG. It is clear that the Romano-Ward syndrome (with at least five different loci) and the JLNS (with at least two different loci; KVLQT1 and KCNE1) are genetically heterogenous [17,24-28]. The most frequent form of the LQTS is the RomanoWard syndrome; the JLNS is a rarer but more malignant variant. Beta-adrenergic blocking drugs serve as the foundation for treatment in symptomatic patients with a history of syncope or aborted cardiac arrest and in some asymptomatic LQTS patients who are members of high-risk families. Left cervicothoracic stellate ganglionectomy has been used effectively in high-risk patients with recurrent syncope uncontrolled by beta-blocking agents and pacemakers. The transvenous implantable cardioverter defibrillator devices have been used effectively in selected highrisk patients with disease refractory to more conventional forms of therapy [29,30]. The children with JLNS in this study were treated with a beta-blocking drug for 8 months. The authors did not observe any cardiac problems, and the QT intervals were shortened with treatment. Whenever a child with CHL presents with attacks of unconsciousness that precede seizures responsive to antiepileptic drugs but the attacks of unconsciousness continue and the family history includes sudden unexplained deaths, the LQTS is a strong possible cause, and cardiac screening should be carefully performed. References [1] Romano C, Gemme G, Pongiglione R. Aritmie cardiache rare dell’eta’pediatrica. Clin Pediatr (Bologna) 1963;45:656-83. [2] Ward OC. A new familial cardiac syndrome in children. J Irish Med Assoc 1964;54:103-6. [3] Jervell A, Lang-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the QT interval and sudden death. Am Heart J 1957;54:59-68. [4] Cusimano F, Martines E, Rizzo C. Jervell and Lang-Nielsen syndrome. Int J Pediatr Otorhinolaryngol 1991;22:49-58. [5] Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920;7:353-70. [6] Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome. An update. Circulation 1993;88: 782-4. [7] Vincent MG, Timothy WK, Leppert M, Keating M. The spectrum of symptoms and QT intervals in carriers of the gene for the long QT syndrome. N Engl J Med 1992;327:846-52. [8] Schwartz PJ, Pereti M, Malliani A. The long QT syndrome. Am Heart J 1975;89:378-90. [9] Day CP, McComb JM, Campbell RWF. QT dispersion: An indication of arrhythmia risk in patients with long QT intervals. Br Heart J 1990;63:342-4.
[10] Barr CS, Naas A, Freeman M, Lang CC, Struthers AD. QT dispersion and sudden death in heart failure. Lancet 1994;343:327-9. [11] Perkiomaki JS, Koistinen J, Yli-Mayry S, Huikuri HV. Dispersion of QT interval in patients with and without susceptibility to ventricular tachyarrhythmias after previous myocardial infarction. J Am Coll Cardiol 1995;267:174-9. [12] Merx W, Yoon MS, Han J. The role of local disparity in conduction and recovery time or ventricular vulnerability to fibrillation. Am Heart J 1977;94:603-10. [13] Kuo CS, Reddy CP, Munakata K, Surawicz B. Mechanism of ventricular arrhythmias caused by increased dispersion of repolarization. Eur Heart J 1985;6 (Suppl D):63-70. [14] Vassallo JA, Cassidy DM, Kindwall KE, Marchlinski FE, Josephson ME. Nonuniform recovery of excitability in the left ventricle. Circulation 1988;78:1365-72. [15] Fraser GR, Froggat P, Murphy T. Genetics aspects of the cardioauditory syndrome of Jervell and Lange-Nielsen (congenital deafness and electrocardiographic abnormalities). Ann Hum Genet 1964;28: 133-57. [16] Hashiba K. Hereditary QT prolongation syndrome in Japan: Genetic analysis and pathologic findings of the conducting system. Jpn Circ J 1978;42:1133-9. [17] Duggal P, Vesely MR, Wattanasirichaigoon D, Villafane J, Kaushik V. Mutation of the gene for IsK associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long QT syndrome. Circulation 1998;97:142-6. [18] Komsuoglu B, Goldeli O, Kulan K, et al. The Jervell and Lange-Nielsen syndrome. Int J Cardiol 1994;47:189-92. [19] Balbir S, Saad AS, Moh’d AH, Saleh MD, Nabil B. Idiopathic long QT syndrome: Asking the right question. Lancet 1993;341:741-2. [20] Neyround N, Tesson F, Denjoy I. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen syndrome. Nat Genet 1997;15:186-9. [21] Keating M, Atkinson D, Dunn C, Timothy K, Vincent GM, Leppert M. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene. Science 1991;252:704-6. [22] Curran ME, Atkinson D, Timothy K, et al. Locus heterogeneity of dominant long QT syndrome. J Clin Invest 1993;92:799-803. [23] Dean JC, Cross S, Jennings K. Evidence of genetic and phenotypic heterogeneity in the Romano-Ward syndrome. J Med Genet 1993;30:947-50. [24] Akimoto K, Matsuoka R, Kasanuki H, et al. Linkage analysis in a Japanese long QT syndrome family. Kokyuto Junkan 1993;41:463-5. [25] Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 1995;80:795-803. [26] Wang Q, Curran ME, Splawski I, et al. Positional cloning of the novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 1996;12:17-23. [27] Wang Q, Shen J, Splawski I, et al. SCNA5 mutations associated with inherited cardiac arrhythmia, long QT syndrome. Cell 1995;80:805-11. [28] Schott J, Charpentier F, Peltier S, et al. Mapping of a gene for long QT syndrome to chromosome 4q25-27. Am J Hum Genet 1995;57: 1114-22. [29] Schwartz PJ, Locati E, Moss AJ. Left cardiac sympathetic denervation in the therapy of the congenital long QT syndrome: A worldwide report. Circulation 1991;84:503-11. [30] Ouriel K, Moss AJ. Long QT syndrome: An indication for cervicothoracic sympathectomy. Cardiovasc Surg 1995;3:475-8.
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