Skip to main content
AAN.com
Articles
November 26, 2008

Identification of a possible pathogenic link between congenital long QT syndrome and epilepsy

January 20, 2009 issue
72 (3) 224-231

Abstract

Background: Long QT syndrome (LQTS) typically presents with syncope, seizures, or sudden death. Patients with LQTS have been misdiagnosed with a seizure disorder or epilepsy and treated with antiepileptic drug (AED) medication. The gene, KCNH2, responsible for type 2 LQTS (LQT2), was cloned originally from the hippocampus and encodes a potassium channel active in hippocampal astrocytes. We sought to test the hypothesis that a “seizure phenotype” was ascribed more commonly to patients with LQT2.
Methods: Charts were reviewed for 343 consecutive, unrelated patients (232 females, average age at diagnosis 27 ± 18 years, QTc 471 ± 57 msec) clinically evaluated and genetically tested for LQTS from 1998 to 2006 at two large LQTS referral centers. A positive seizure phenotype was defined as the presence of either a personal or family history of seizures or history of AED therapy.
Results: A seizure phenotype was recorded in 98/343 (29%) probands. A seizure phenotype was more common in LQT2 (36/77, 47%) than LQT1 (16/72, 22%, p < 0.002) and LQT3 (7/28, 25%, p < 0.05, NS). LQT1 and LQT3 combined cohorts did not differ significantly from expected, background rates of a seizure phenotype. A personal history of seizures was more common in LQT2 (30/77, 39%) than all other subtypes of LQTS (11/106, 10%, p < 0.001).
Conclusions: A diagnostic consideration of epilepsy and treatment with antiepileptic drug medications was more common in patients with LQT2. Like noncardiac organ phenotypes observed in other LQTS-susceptibility genes such as KCNQ1/deafness and SCN5A/gastrointestinal symptoms, this novel LQT2-epilepsy association raises the possibility that LQT2-causing perturbations in the KCNH2-encoded potassium channel may confer susceptibility for recurrent seizure activity.

Get full access to this article

View all available purchase options and get full access to this article.

Supplementary Material

File (johnson.pdf)

REFERENCES

1.
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.
2.
Romano C, Gemme G, Pongiglione R. Rare cardiac arrhythmias of the pediatric age: II: syncopal attacks due to paroxysmal ventricular fibrillation (presentation of 1st case in Italian pediatric literature) Clin Pediatr (Bologna) 1963;45:656–683.
3.
Ward OC. A new familial cardiac syndrome in children. J Ir Med Assoc 1964;54:103–106.
4.
Ackerman M.J. The long QT syndrome: ion channel diseases of the heart. Mayo Clin Proc 1998;73:250–269.
5.
Vatta M, Ackerman MJ, Ye B, et al. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation 2006;114:2104–2112.
6.
Mohler PJ, Schott JJ, Gramolini AO, et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature 2003;421:634–639.
7.
Ackerman M.J: Cardiac channelopathies: it's in the genes. Nat Med 2004;10:463–464.
8.
Moss AJ, Robinson JL. Clinical aspects of the idiopathic long QT syndrome. Ann NY Acad Sci 1992;644:103–111.
9.
Vincent GM, Timothy K, Fox J, Zhang L. The inherited long QT syndrome: from ion channel to bedside. Cardiol Rev 1999;7:44–55.
10.
Vincent GM, Timothy KW, 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;327:846–852.
11.
Ackerman MJ. Genotype–phenotype relationships in congenital long QT syndrome. J Electrocardiol 2005;38(4 suppl):64–68.
12.
Van Langen IM, Birnie E, Alders M, Jongbloed RJ, Le Marec H, Wilde AA. The use of genotype–phenotype correlations in mutation analysis for the long QT syndrome. J Med Genet 2003;40:141–145.
13.
Choi G, Kopplin LJ, Tester DJ, Will ML, Haglund CM, Ackerman MJ. Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes. Circulation 2004;110:2119–2124.
14.
Ackerman MJ, Tester DJ, Porter CJ. Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome. Mayo Clin Proc 1999;74:1088–1094.
15.
Rashba EJ, Zareba W, Moss AJ, et al. Influence of pregnancy on the risk for cardiac events in patients with hereditary long QT syndrome. LQTS Investigators. Circulation 1998;97:451–456.
16.
Tester DJ, Will ML, Haglund CM, Ackerman MJ. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm 2005;2:507–517.
17.
Khositseth A, Tester DJ, Will ML, Bell CM, Ackerman MJ. Identification of a common genetic substrate underlying postpartum cardiac events in congenital long QT syndrome. Heart Rhythm 2004;1:60–64.
18.
Wilde AA, Jongbloed RJ, Doevendans PA, et al. Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1). J Am Coll Cardiol 1999;33:327–332.
19.
Tan HL, Bardai A, Shimizu W, et al. Genotype-specific onset of arrhythmias in congenital long-QT syndrome: possible therapy implications. Circulation 2006;114:2096–2103.
20.
Locke GR, 3rd, Ackerman MJ, Zinsmeister AR, Thapa P, Farrugia G. Gastrointestinal symptoms in families of patients with an SCN5A-encoded cardiac channelopathy: evidence of an intestinal channelopathy. Am J Gastroenterol 2006;101:1299–1304.
21.
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.
22.
Titus SA, Warmke JW, Ganetzky B. The Drosophila erg K+ channel polypeptide is encoded by the seizure locus. J Neurosci 1997;17:875–881.
23.
Warmke JW, Ganetzky B. A family of potassium channel genes related to EAG in Drosophila and mammals. Proc Natl Acad Sci USA 1994;91:3438–3442.
24.
Emmi A, Wenzel HJ, Schwartzkroin PA, et al. Do glia have heart? Expression and functional role for ether-a-go-go currents in hippocampal astrocytes. J Neurosci 2000;20:3915–3925.
25.
Linden DJ. Long-term potentiation of glial synaptic currents in cerebellar culture. Neuron 1997;18:983–994.
26.
Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci 1999;22:208–215.
27.
D'Ambrosio R, Maris DO, Grady MS, Winn HR, Janigro D. Impaired K(+) homeostasis and altered electrophysiological properties of post-traumatic hippocampal glia. J Neurosci 1999;19:8152–8162.
28.
Bazett H. An analysis of the time-relations of electrocardiograms. Heart 1920; 7:353–370.
29.
Horn CA, Beekman RH, Dick M 2nd, Lacina SJ. The congenital long QT syndrome: an unusual cause of childhood seizures. Am J Dis Child 1986;140:659–661.
30.
Seth R, Moss AJ, McNitt S, et al. Long QT syndrome and pregnancy. J Am Coll Cardiol 2007;49:1092–1098.
31.
Donahue LM, Coates PW, Lee VH, Ippensen DC, Arze SE, Poduslo SE. The cardiac sodium channel mRNA is expressed in the developing and adult rat and human brain. Brain Res 2000;887:335–343.
32.
Biervert C, Schroeder BC, Kubisch C, et al. A potassium channel mutation in neonatal human epilepsy. Science 1998;279:403–6.
33.
Charlier C, Singh NA, Ryan SG, et al. A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat Genet 1998;18:53–5.
34.
Singh NA, Charlier C, Stauffer D, et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet 1998;18:25–29.
35.
Noebels JL. Sodium channel gene expression and epilepsy. Novartis Found Symp 2002; 241:109–120; discussion 120–123, 226–232.
36.
Janigro D, Gasparini S, D'Ambrosio R, McKhann G, 2nd, DiFrancesco D. Reduction of K+ uptake in glia prevents long-term depression maintenance and causes epileptiform activity. J Neurosci 1997;17:2813–2824.
37.
Kofuji P, Newman EA. Potassium buffering in the central nervous system. Neuroscience 2004;129:1045–1056.
38.
Papa M, Boscia F, Canitano A, et al. Expression pattern of the ether-a-gogo-related (ERG) K+ channel-encoding genes ERG1, ERG2, and ERG3 in the adult rat central nervous system. J Comp Neurol 2003;466:119–135.
39.
Danielsson BR, Lansdell K, Patmore L, Tomson T. Phenytoin and phenobarbital inhibit human HERG potassium channels. Epilepsy Res 2003;55:147–157.

Information & Authors

Information

Published In

Neurology®
Volume 72Number 3January 20, 2009
Pages: 224-231
PubMed: 19038855

Publication History

Published online: November 26, 2008
Published in print: January 20, 2009

Permissions

Request permissions for this article.

Notes

Authors

Affiliations & Disclosures

J. N. Johnson, MD
From the Department of Pediatrics/Division of Pediatric Cardiology (J.N.J., C.M.H., M.J.A.), Department of Molecular Pharmacology and Experimental Therapeutics (C.M.H., M.J.A.), Department of Neurology/Division of Epilepsy (G.D.C.), and Department of Medicine/Division of Cardiovascular Diseases (M.J.A.), Mayo Clinic, Rochester, MN; and Departments of Clinical Genetics (N.H.) and Cardiology (A.A.M.W.), Academic Medical Center, Amsterdam, The Netherlands.
N. Hofman, MSc
From the Department of Pediatrics/Division of Pediatric Cardiology (J.N.J., C.M.H., M.J.A.), Department of Molecular Pharmacology and Experimental Therapeutics (C.M.H., M.J.A.), Department of Neurology/Division of Epilepsy (G.D.C.), and Department of Medicine/Division of Cardiovascular Diseases (M.J.A.), Mayo Clinic, Rochester, MN; and Departments of Clinical Genetics (N.H.) and Cardiology (A.A.M.W.), Academic Medical Center, Amsterdam, The Netherlands.
C. M. Haglund
From the Department of Pediatrics/Division of Pediatric Cardiology (J.N.J., C.M.H., M.J.A.), Department of Molecular Pharmacology and Experimental Therapeutics (C.M.H., M.J.A.), Department of Neurology/Division of Epilepsy (G.D.C.), and Department of Medicine/Division of Cardiovascular Diseases (M.J.A.), Mayo Clinic, Rochester, MN; and Departments of Clinical Genetics (N.H.) and Cardiology (A.A.M.W.), Academic Medical Center, Amsterdam, The Netherlands.
G. D. Cascino, MD, FAAN
From the Department of Pediatrics/Division of Pediatric Cardiology (J.N.J., C.M.H., M.J.A.), Department of Molecular Pharmacology and Experimental Therapeutics (C.M.H., M.J.A.), Department of Neurology/Division of Epilepsy (G.D.C.), and Department of Medicine/Division of Cardiovascular Diseases (M.J.A.), Mayo Clinic, Rochester, MN; and Departments of Clinical Genetics (N.H.) and Cardiology (A.A.M.W.), Academic Medical Center, Amsterdam, The Netherlands.
A.A.M. Wilde, MD, PhD
From the Department of Pediatrics/Division of Pediatric Cardiology (J.N.J., C.M.H., M.J.A.), Department of Molecular Pharmacology and Experimental Therapeutics (C.M.H., M.J.A.), Department of Neurology/Division of Epilepsy (G.D.C.), and Department of Medicine/Division of Cardiovascular Diseases (M.J.A.), Mayo Clinic, Rochester, MN; and Departments of Clinical Genetics (N.H.) and Cardiology (A.A.M.W.), Academic Medical Center, Amsterdam, The Netherlands.
M. J. Ackerman, MD, PhD
From the Department of Pediatrics/Division of Pediatric Cardiology (J.N.J., C.M.H., M.J.A.), Department of Molecular Pharmacology and Experimental Therapeutics (C.M.H., M.J.A.), Department of Neurology/Division of Epilepsy (G.D.C.), and Department of Medicine/Division of Cardiovascular Diseases (M.J.A.), Mayo Clinic, Rochester, MN; and Departments of Clinical Genetics (N.H.) and Cardiology (A.A.M.W.), Academic Medical Center, Amsterdam, The Netherlands.

Notes

Address correspondence and reprint requests to Dr. Michael J. Ackerman, Director, Long QT Syndrome Clinic and the Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Guggenheim 501, 200 First Street SW, Rochester, MN 55905 [email protected].

Metrics & Citations

Metrics

Citations

Download Citations

If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.

Cited By
  1. Electrocardiogram Changes in the Postictal Phase of Epileptic Seizure: Results from a Prospective Study, Journal of Clinical Medicine, 12, 12, (4098), (2023).https://doi.org/10.3390/jcm12124098
    Crossref
  2. It is premature for a unified hypothesis of sudden unexpected death in epilepsy: A great amount of research is still needed to understand the multisystem cascade , Epilepsia, 64, 8, (2006-2010), (2023).https://doi.org/10.1111/epi.17636
    Crossref
  3. The role of the adenosine system in epilepsy and its comorbidities, British Journal of Pharmacology, (2023).https://doi.org/10.1111/bph.16094
    Crossref
  4. SCN5A channelopathy: arrhythmia, cardiomyopathy, epilepsy and beyond , Philosophical Transactions of the Royal Society B: Biological Sciences, 378, 1879, (2023).https://doi.org/10.1098/rstb.2022.0164
    Crossref
  5. KCNH2 encodes a nuclear-targeted polypeptide that mediates hERG1 channel gating and expression , Proceedings of the National Academy of Sciences, 120, 3, (2023).https://doi.org/10.1073/pnas.2214700120
    Crossref
  6. Measuring vagal activity in postictal bradycardia, Epilepsy & Behavior, 141, (109148), (2023).https://doi.org/10.1016/j.yebeh.2023.109148
    Crossref
  7. Sudden cardiac arrest in infants and children: proposal for a diagnostic workup to identify the etiology. An 18-year multicenter evaluation in the Netherlands, European Journal of Pediatrics, (2023).https://doi.org/10.1007/s00431-023-05301-9
    Crossref
  8. KCNH2 variants in a family with epilepsy and long QT syndrome: A case report and literature review , Epileptic Disorders, 25, 4, (492-499), (2023).https://doi.org/10.1002/epd2.20046
    Crossref
  9. Locus Coeruleus Neurons’ Firing Pattern Is Regulated by ERG Voltage-Gated K+ Channels, International Journal of Molecular Sciences, 23, 23, (15334), (2022).https://doi.org/10.3390/ijms232315334
    Crossref
  10. The ERG1 K+ Channel and Its Role in Neuronal Health and Disease, Frontiers in Molecular Neuroscience, 15, (2022).https://doi.org/10.3389/fnmol.2022.890368
    Crossref
  11. See more
Loading...

View Options

Get Access

Login options

Check if you have access through your login credentials or your institution to get full access on this article.

Personal login Institutional Login
Purchase Options

Purchase this article to get full access to it.

Purchase Access, $39 for 24hr of access

View options

Full Text

View Full Text

Full Text HTML

View Full Text HTML

Media

Figures

Other

Tables

Share

Share

Share article link

Share