Original Article
Brief Report
A Molecular Link between the Sudden Infant Death Syndrome and the Long-QT Syndrome
N Engl J Med 2000; 343:262-267July 27, 2000
- Article
The sudden infant death syndrome (SIDS) remains the leading cause of death in the first year of life and has a devastating impact on the affected families.1-4 Despite the fact that there have been many hypotheses,3,4 the cause or causes of SIDS are still uncertain; as a consequence, the only preventive measure recommended is to avoid having infants sleep in a prone position.5
In 1998, we reported the results of a 19-year prospective study of more than 34,000 infants who underwent electrocardiography on the third or fourth day of life.6 We tested the hypothesis7,8 that the congenital long-QT syndrome accounts for a portion of the cases of SIDS.9,10 We found that 50 percent of the infants who died of SIDS had a prolonged QT interval corrected for heart rate (QTc) and that the presence of a prolonged QTc (>440 msec) in the first week of life increased the risk of SIDS by a factor of 41.6 This finding had implications with respect to the potential value of neonatal electrocardiographic screening.
Among the hypotheses that we had advanced to explain the origin of a prolonged QT interval in infants, its relation to the increased risk of sudden death, and the fact that the parents of these infants had apparently normal electrocardiograms, two were testable. The first was that a spontaneous mutation occurs in one of the genes responsible for the long-QT syndrome,11 and the second was that these infants are affected by a long-QT syndrome with a low penetrance.12
In this report we describe an infant who nearly died of SIDS, whose parents had normal QT intervals, and in whom the long-QT syndrome was diagnosed and a spontaneous mutation on the cardiac sodium-channel gene (SCN5A) was identified. Neonatal electrocardiographic screening would have made possible early identification of the prolonged long-QT interval and preventive treatment of this infant. Our findings in this single case report prove the validity of our first hypothesis and provide evidence of a link between the long-QT syndrome and SIDS. Our findings also demonstrate that spontaneous mutations in long-QT syndrome genes may manifest as and be indistinguishable from classic cases of near-SIDS or of SIDS itself.
Case Report
On October 19, 1995, the parents of a 44-day-old infant who had a completely normal clinical history found him cyanotic, apneic, and pulseless. They rushed him to the emergency room of the local hospital, where an electrocardiogram showed ventricular fibrillation (Figure 1AFigure 1
Electrocardiograms at the Time of Admission to the Hospital (Panel A), after the Restoration of Sinus Rhythm (Panel B), and at the Time of the Last Follow-up Visit (Panel C).). Multiple DC shocks and mechanical ventilation were needed to restore sinus rhythm, and a marked prolongation of the QT interval was documented (QTc, 648 msec) (Figure 1B). The plasma electrolyte levels were normal. Torsade de pointes recurred several times, often degenerating into ventricular fibrillation. The long-QT syndrome was diagnosed, treatment with propranolol (4 mg per kilogram of body weight) and mexiletine (10 mg per kilogram) was begun, and there were no recurrences of arrhythmias. At nearly five years of age, the child remains free of symptoms, and there have been no neurologic sequelae. At the time of the last follow-up examination at our institution, when he was three years old, the QT interval was still prolonged, but less severely so (QTc, 510 msec) (Figure 1C). The child had no family history of the long-QT syndrome or SIDS, and the QT intervals of both his parents were within normal limits: his mother's QTc was 380 msec, and his father's QTc was 425 msec.Methods
Molecular Screening
Genomic DNA was extracted from peripheral-blood lymphocytes from the child and his parents with the use of standard techniques.13 Screening for mutations was performed in all genes known to be related to the long-QT syndrome with the use of specific oligonucleotide primer pairs.14,15 Single-strand conformational polymorphism analysis16 was used as a preliminary screening technique. Samples with mobility shifts were sequenced directly or were subcloned into a pBlueScript Sk– vector (Stratagene, La Jolla, Calif.) and then sequenced. Multiple sequences were compared with use of computer software (GCG Wisconsin Sequence Analysis Package, version 8.1, Genetics Computers Group, Palo Alto, Calif.).
Gene-Expression Studies
The normal, or wild-type, human-heart sodium-channel clone (hH1a) that we used has been described previously.17,18 The SIDS-LQTS mutation consisted of the substitution of AAC for TCC at positions 2971 to 2972 and was introduced into the wild-type construct by site-directed polymerase-chain-reaction mutagenesis19 and verified by sequencing. In vitro transcription of coding RNA, heterologous expression of the transcripts in xenopus oocytes, and electrophysiologic measurements were performed at room temperature, as described previously.17 We measured the amplitude of the late sodium current 300 msec after the beginning of the test pulse. Measurements made at the 300-msec isochrone are representative of the amplitude expected during the plateau (phase 2) of the ventricular action potential. We measured the late current as the current that was tetrodotoxin-sensitive and expressed it as the percentage of the peak current at the same voltage.
Results
Molecular Screening
The substitution of two nucleotides (AAC for TCC) at the same codon (positions 2971 to 2972) was found in exon 16 of the coding sequence of SCN5A (Figure 2Figure 2
Results of Molecular Screening.) in genomic DNA from the child. These changes lead to the substitution of a single amino acid — asparagine (N) replaces serine (S) — at codon 941 (S941N). The AA portion of nucleotide 941 lies in the intracellular loop between the second and third transmembrane domains of SCN5A. 14 This area is highly conserved in different species. The mutation was not found in 400 chromosomes obtained from 200 reference subjects.Molecular screening of genomic DNA from the child's parents showed that neither had the S941N mutation. A set of highly polymorphic microsatellite markers was used to confirm paternity, thus demonstrating that the child had a spontaneous mutation in a gene for the long-QT syndrome.
Gene-Expression Studies
When expressed in frog oocytes, the S941N mutation in SCN5A caused a gradual increase in the amplitude of the late sodium current (from 179 percent at –20 mV to 249 percent at 20 mV) (Figure 3Figure 3
Effect of the S941N Mutation in SCN5A on Depolarization.). At a voltage of 10 mV, which typically is present at the end of phase 2 of the ventricular action potential, the peak current was 33 μA and the conductance of the mutant late sodium channels was increased by a mean factor of 2.4 (237 percent) as compared with that of the wild-type channels.Discussion
The findings in this case report provide evidence that a life-threatening event in infancy, with features that meet all the criteria for SIDS or for near-SIDS, may be due to a spontaneous mutation in genes for the long-QT syndrome, which is therefore not present in the parents of the infant and which leads to sudden death as a result of ventricular fibrillation. Our findings also provide evidence of one of the mechanisms involved in SIDS, have implications with respect to the difficult issue of widespread electrocardiographic screening of neonates, and indicate that at least this subtype can be diagnosed and prevented.
This case has all the classic features of near-SIDS. Before the episode, the infant had appeared to be in perfect health. His age at the time of the episode — 7 weeks — is within the age range of 5 to 12 weeks during which the incidence of SIDS peaks.2 The parents found him cyanotic, apneic, and pulseless and rushed him to the hospital while attempting cardiopulmonary resuscitation: this is the same sequence of events described by the parents of infants who have died of SIDS and of those who have nearly died. Ventricular fibrillation was documented in the emergency room; this point is important given the frequent statements that ventricular arrhythmias have not been recorded in infants at risk for SIDS. Had the infant died — an outcome that was almost a certainty in the absence of cardioversion — the absence of an electrocardiogram and the normal QT intervals of both parents would have eliminated suspicion of the long-QT syndrome and would have prompted a diagnosis of SIDS.
The finding, after restoration of sinus rhythm, that the QT interval was greatly prolonged led to the diagnosis of the long-QT syndrome and to the institution of a therapy that proved to be effective, since the patient had no documented or symptomatic recurrences of arrhythmia. The long-QT syndrome may become apparent in the first few months of life20 and can be diagnosed at birth, usually on the basis of a finding of bradycardia resulting from a 2:1 atrioventricular block21 or of tachyarrhythmias; commonly, one parent has a prolonged QT interval. In our patient, both parents had normal QT intervals; thus, the diagnosis of the long-QT syndrome rested exclusively on the availability of the electrocardiographic findings.
Molecular screening of the patient and his parents provided the key to understanding how infants whose parents are unaffected die suddenly of the long-QT syndrome. The absence of the mutation in both parents and confirmation of paternity were essential to establish that the infant had a spontaneous mutation of a gene for the long-QT syndrome. All such genes identified to date encode ion channels involved in the control of ventricular repolarization.11 The mutation found in this infant is in SCN5A, the cardiac sodium-channel gene responsible for the LQT3 subtype of the long-QT syndrome11 and for the Brugada syndrome,22 another potential cause of sudden death in infancy.23 Interestingly, patients with the subtype LQT3 have a further prolongation of the QT interval at night24 and are particularly likely to die while at rest or in their sleep25 and during their first arrhythmic episode.26 The administration of sodium-channel blockers such as mexiletine shortens the QT interval in these patients27 and may prevent the arrhythmias.28
Dumaine et al.29 showed that R1644H, another mutation known to cause the LQT3 subtype, increased the amplitude of the late sodium current by a factor of 2.3 under experimental conditions that were identical to ours. The increase in the amplitude of the late sodium current induced by the S941N mutation is therefore similar to that observed for other mutations known to give rise to the LQT3 subtype and is likely to be the basis for the prolongation of the QT interval observed in our patient. This late sodium current contributes prominently to the maintenance of phase 2 of the ventricular action potential, and thus, to its prolongation.30 This finding links this case of near-SIDS to a defect in an ion channel associated with the long-QT syndrome.
The postmortem examination of patients who have died of SIDS and of those who have died of the long-QT syndrome usually fails to establish an abnormality sufficient to cause death. Recent data10 indicate that 14 percent of all patients with the long-QT syndrome die during their first episode of arrhythmia and that 30 percent of these deaths occur during the first year of life. If these patients had not been identified as having a family history of the long-QT syndrome, death would have been attributed to SIDS.
The case of our patient is unique because a molecular diagnosis of the long-QT syndrome was made in a patient who had all the key features of SIDS. How many similar cases go unrecognized? Maron et al.31 described an infant who also presented at six weeks of age after nearly dying of SIDS, who had a markedly prolonged QTc (570 msec), who underwent defibrillation, and who led an active life without therapy despite the persistence of borderline prolongation of the QTc (460 msec) until she died in her sleep at the age of 12. This was apparently a case of the long-QT syndrome — possibly subtype LQT3, given her ability to participate in sports and the fact that she died during sleep.25 It is important — and consistent with the occurrence of a spontaneous mutation — that all 18 of her first-degree relatives had a normal QT interval.
Data from almost 1000 families with a history of the long-QT syndrome indicate that treatment with beta-blockers reduces the mortality rate below 3 percent.10 This information is relevant to the prevention of SIDS in newborns with a prolonged QT interval, since it may provide a valid therapy in patients identified by neonatal screening as being at risk.
SIDS is multifactorial; the long-QT syndrome can account for only a fraction of the cases, and precise quantification of this fraction remains difficult despite the data obtained from our large epidemiologic study.6 The practical importance of this concept lies in the fact that most deaths due to the long-QT syndrome can be prevented.9,10 This implies that if the infants at risk were identified early on the basis of a consistently prolonged QT interval, preventive therapy could be instituted for a few months. Normalization of the QT interval during development would allow the withdrawal of therapy in the unavoidably large number of false positives while therapy might continue to protect the truly affected infants.
This case raises disquieting issues. Prompt defibrillation and restoration of sinus rhythm in our patient allowed the diagnosis of the long-QT syndrome to be made and lifesaving therapy to be instituted. The infant, however, could have died or could have suffered irreversible brain damage as a result of prolonged cardiac arrest; in the latter case, electrocardiography would still have led to the diagnosis. Undeniably, neonatal electrocardiography would have led to a much earlier diagnosis and institution of therapy and almost certainly would have prevented the life-threatening episode. Much of the current controversy surrounding neonatal electrocardiographic screening concerns the high number of false positives. This number could be decreased by postponing the screening until the second or third week of life. What has not been considered in the discussion is the emotional impact and the medicolegal consequences of cases such as the present one, in which diagnosis would be easy and treatment lifesaving. Myerburg32 has correctly stated that whether the cost of saving a young life exceeds the economic inefficiency of the screening tool will need to be determined by society as a whole.
Supported in part by a contract (BMH4-CT96-0028) with the European Commission and by a grant (1058) from Telethon.
We are indebted to Stacy A. Scicchitano for her contribution to the genetic-expression studies and to Pinuccia De Tomasi for expert editorial support.
Source Information
From the Department of Cardiology, University of Pavia and Policlinico San Matteo Istituto di Ricovero e Cura a Carattere Scientifico, Pavia, Italy (P.J.S., S.G.P., R.B.); the Molecular Cardiology and Electrophysiology Laboratory, Fondazione Salvatore Maugeri Istituto di Ricovero e Cura a Carattere Scientifico, Pavia, Italy (S.G.P., C.N.); the Department of Molecular Biology, Masonic Medical Research Laboratory, Utica, N.Y. (R.D., C.A., T.A.R.); the Centro di Fisiologia Clinica e Ipertensione, University of Milan, Ospedale Maggiore Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy (C.N.); the Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Luca, Istituto Auxologico Italiano, Milan, Italy (M.S.-B.); and the Unità Operativa di Neonatologia, Ospedale S. Chiara, Trento, Italy (M.R.B.).
Address reprint requests to Dr. Schwartz at the Department of Cardiology, Policlinico San Matteo IRCCS, Viale Golgi, 19-27100 Pavia, Italy, or at pjqt@compuserve.com.
- References
References
1
Valdes-Dapena MA . Sudden, unexpected and unexplained death in infancy -- a status report -- 1973. N Engl J Med 1973;289:1195-1197
Full Text | Web of Science | Medline2
Schwartz PJ. The sudden infant death syndrome. In: Scarpelli EM, Cosmi EV, eds. Reviews in perinatal medicine. Vol. 4. New York: Raven Press, 1981:475-524.
3
Schwartz PJ . The quest for the mechanisms of the sudden infant death syndrome: doubts and progress. Circulation 1987;75:677-683
CrossRef | Web of Science | Medline4
Schwartz PJ ,Southall DP ,Valdes-Dapena M , eds. The sudden infant death syndrome: cardiac and respiratory mechanisms and interventions. Ann N Y Acad Sci 1988;533:1-474
CrossRef | Web of Science5
Dwyer T ,Ponsonby AL ,Blizzard L ,Newman NM ,Cochrane JA . The contribution of changes in the prevalence of prone sleeping position to the decline in sudden infant death syndrome in Tasmania. JAMA 1995;273:783-789
CrossRef | Web of Science | Medline6
Schwartz PJ ,Stramba-Badiale M ,Segantini A , et al. Prolongation of the QT interval and the sudden infant death syndrome. N Engl J Med 1998;338:1709-1714
Full Text | Web of Science | Medline7
Schwartz PJ. Experimental reproduction of long QT syndrome and SIDS, 1974. (NIH grant application no. NIH CHD08796.)
8
Schwartz PJ . Cardiac sympathetic innervation and the sudden infant death syndrome: a possible pathogenetic link. Am J Med 1976;60:167-172
CrossRef | Web of Science | Medline9
Schwartz PJ . Idiopathic long QT syndrome: progress and questions. Am Heart J 1985;109:399-411
CrossRef | Web of Science | Medline10
Schwartz PJ, Priori SG, Napolitano C. The long QT syndrome. In: Zipes DP, Jalife J, eds. Cardiac electrophysiology: from cell to bedside. 3rd ed. Philadelphia: W.B. Saunders, 2000:597-615.
11
Priori SG ,Barhanin J ,Hauer RNW , et al. Genetic and molecular basis of cardiac arrhythmias: impact on clinical management. Circulation 1999;99:518-28, 674
Web of Science | Medline12
Priori SG ,Napolitano C ,Schwartz PJ . Low penetrance in the long-QT syndrome: clinical impact. Circulation 1999;99:529-533
Web of Science | Medline13
Sambrook J, Fritsch EF, Maniatis T. Molecular cloning: a laboratory manual. 2nd ed. Plainview, N.Y.: Cold Spring Harbor Laboratory Press, 1989.
14
Wang Q ,Li Z ,Shen J ,Keating MT . Genomic organization of the human SCN5A gene encoding the cardiac sodium channel. Genomics 1996;34:9-16
CrossRef | Web of Science | Medline15
Splawski I ,Shen J ,Timothy KW ,Vincent GM ,Lehmann MH ,Keating MT . Genomic structure of three long QT syndrome genes: KvLQT1, HERG, and KCNE1. Genomics 1998;51:86-97
CrossRef | Web of Science | Medline16
Orita M ,Iwahana H ,Kanazawa H ,Hayashi K ,Sekiya T . Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci U S A 1989;86:2766-2770
CrossRef | Web of Science | Medline17
Hartmann HA ,Tiedeman AA ,Chen S-F ,Brown AM ,Kirsch GE . Effects of III-IV linker mutations on human heart Na+ channel inactivation gating. Circ Res 1994;75:114-122
Web of Science | Medline18
Gellens ME ,George AL Jr ,Chen LQ , et al. Primary structure and functional expression of the human cardiac tetrodotoxin-insensitive voltage-dependent sodium channel. Proc Natl Acad Sci U S A 1992;89:554-558
CrossRef | Web of Science | Medline19
Sarkar G ,Sommer SS . The “megaprimer“ method of site-directed mutagenesis. Biotechniques 1990;8:404-407
Web of Science | Medline20
Romano C ,Gemme G ,Pongiglione R . Aritmie cardiache rare dell'età pediatrica. Clin Pediatr (Bologna) 1963;45:656-683
Medline21
Gorgels APM ,Al Fadley F ,Zaman L ,Kantoch MJ ,Al Halees Z . The long QT syndrome with impaired atrioventricular conduction: a malignant variant in infants. J Cardiovasc Electrophysiol 1998;9:1225-1232
CrossRef | Web of Science | Medline22
Chen Q ,Kirsch GE ,Zhang D , et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 1998;392:293-296
CrossRef | Web of Science | Medline23
Priori SG ,Napolitano C ,Giordano U ,Collisani G ,Memmi M . Brugada syndrome and sudden cardiac death in children. Lancet 2000;355:808-809
CrossRef | Web of Science | Medline24
Stramba-Badiale M ,Priori SG ,Napolitano C , et al. Gene-specific differences in the circadian variation of ventricular repolarization in the long QT syndrome: a key to sudden death during sleep? Ital Heart J 2000;1:323-328
Medline25
Schwartz PJ ,Moss AJ ,Priori SG , et al. Gene-specific influence on the triggers for cardiac arrest in the long QT syndrome. Circulation 1997;96:Suppl I:I-212 abstract.26
Zareba W ,Moss AJ ,Schwartz PJ , et al. Influence of the genotype on the clinical course of the long-QT syndrome. N Engl J Med 1998;339:960-965
Full Text | Web of Science | Medline27
Schwartz PJ ,Priori SG ,Locati EH , et al. Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate: implications for gene-specific therapy. Circulation 1995;92:3381-3386
Web of Science | Medline28
Shimizu W ,Antzelevitch C . Sodium channel block with mexiletine is effective in reducing dispersion of repolarization and preventing torsade de pointes in LQT2 and LQT3 models of the long-QT syndrome. Circulation 1997;96:2038-2047
Web of Science | Medline29
Dumaine R ,Wang Q ,Keating MT , et al. Multiple mechanisms of Na+ channel-linked long-QT syndrome. Circ Res 1996;78:916-924
Web of Science | Medline30
Roden DM ,Lazzara R ,Rosen MR ,Schwartz PJ ,Towbin JA ,Vincent GM . Multiple mechanisms in the long-QT syndrome: current knowledge, gaps, and future directions. Circulation 1996;94:1996-2012
Web of Science | Medline31
Maron BJ ,Barbour DJ ,Marraccini JV ,Roberts WC . Sudden unexpected death 12 years after “near-miss“ sudden infant death syndrome in infancy. Am J Cardiol 1986;58:1104-1105
CrossRef | Web of Science | Medline32
Myerburg RJ. We can prevent sudden death in teenagers. Miami Herald. March 17, 1999.
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Peter J Schwartz, Lia Crotti. (2008) Ion channel diseases in children: manifestations and management. Current Opinion in Cardiology 23:3, 184-191
CrossRef36
Natasa Savic, Ljiljana Gojkovic-Bukarica. (2008) Long QT syndrome: Genetic implications and drug influence. Vojnosanitetski pregled 65:4, 308-312
CrossRef37
Luisa Mestroni, Shelley D. Miyamoto, Matthew R.G. Taylor. (2007) Genetics of dilated cardiomyopathy conduction disease. Progress in Pediatric Cardiology 24:1, 3-13
CrossRef38
Darius A Loghmanee, Debra E Weese-Mayer. (2007) Sudden infant death syndrome: another year of new hope but no cure. Current Opinion in Pulmonary Medicine 13:6, 497-504
CrossRef39
Seo-Kyung Chung, Judith M. MacCormick, Caroline H. McCulley, Jackie Crawford, Carey-Anne Eddy, Edwin A. Mitchell, Andrew N. Shelling, John K. French, Jonathan R. Skinner, Mark I. Rees. (2007) Long QT and Brugada syndrome gene mutations in New Zealand. Heart Rhythm 4:10, 1306-1314
CrossRef40
David Farwell, Michael H Gollob. (2007) Electrical heart disease: Genetic and molecular basis of cardiac arrhythmias in normal structural hearts. Canadian Journal of Cardiology 23, 16A-22A
CrossRef41
Nadine Kiehne, Silke Kauferstein. (2007) Mutations in the SCN5A gene: Evidence for a link between long QT syndrome and sudden death?. Forensic Science International: Genetics 1:2, 170-174
CrossRef42
Peter J. Schwartz, Lia Crotti. (2007) Cardiac arrhythmias of genetic origin are important contributors to sudden infant death syndrome. Heart Rhythm 4:6, 740-742
CrossRef43
David J. Tester, Miroslav Dura, Elisa Carturan, Steven Reiken, Anetta Wronska, Andrew R. Marks, Michael J. Ackerman. (2007) A mechanism for sudden infant death syndrome (SIDS): Stress-induced leak via ryanodine receptors. Heart Rhythm 4:6, 733-739
CrossRef44
Christopher Newton-Cheh, Ripal Shah. (2007) Genetic determinants of QT interval variation and sudden cardiac death. Current Opinion in Genetics & Development 17:3, 213-221
CrossRef45
Horst Wedekind, Eric Schulze-Bahr, Volker Debus, Günter Breithardt, Bernd Brinkmann, Thomas Bajanowski. (2007) Cardiac arrhythmias and sudden death in infancy: implication for the medicolegal investigation. International Journal of Legal Medicine 121:4, 245-257
CrossRef46
Lina Nashef, Neeti Hindocha, Andrew Makoff. (2007) Risk Factors in Sudden Death in Epilepsy (SUDEP): The Quest for Mechanisms. Epilepsia 48:5, 859-871
CrossRef47
Tarique Hussain, Andrew K Ewer. (2007) Maternal methadone may cause arrhythmias in neonates. Acta Paediatrica 96:5, 768-769
CrossRef48
Debra E. Weese-Mayer, Michael J. Ackerman, Mary L. Marazita, Elizabeth M. Berry-Kravis. (2007) Sudden Infant Death Syndrome: Review of implicated genetic factors. American Journal of Medical Genetics Part A 143A:8, 771-788
CrossRef49
Ernest Cutz, Donald G. Perrin, Jie Pan, Elisabeth A. Haas, Henry F. Krous. (2007) Pulmonary Neuroendocrine Cells and Neuroepithelial Bodies in Sudden Infant Death Syndrome: Potential Markers of Airway Chemoreceptor Dysfunction. Pediatric and Developmental Pathology 10:2, 106-116
CrossRef50
Nathalie H. Nielsen, Bo G. Winkel, Jørgen K. Kanters, Nicole Schmitt, Jacob Hofman-Bang, Henrik S. Jensen, Bo H. Bentzen, Bjarne Sigurd, Lars A. Larsen, Paal S. Andersen, Stig Haunsø, Keld Kjeldsen, Morten Grunnet, Michael Christiansen, Søren-Peter Olesen. (2007) Mutations in the Kv1.5 channel gene KCNA5 in cardiac arrest patients. Biochemical and Biophysical Research Communications 354:3, 776-782
CrossRef51
Lisa B. Cronk, Bin Ye, Toshihiko Kaku, David J. Tester, Matteo Vatta, Jonathan C. Makielski, Michael J. Ackerman. (2007) Novel mechanism for sudden infant death syndrome: Persistent late sodium current secondary to mutations in caveolin-3. Heart Rhythm 4:2, 161-166
CrossRef52
Thomas Bajanowski, Åshild Vege, Roger W. Byard, Henry F. Krous, Marianne Arnestad, Liliana Bachs, Jytte Banner, Peter S. Blair, Arne Borthne, Reinhard Dettmeyer, Peter Fleming, Peter Gaustad, Markil Gregersen, Jens Grøgaard, Ellen Holter, Christina V. Isaksen, Jens V. Jorgensen, Charlotte de Lange, Burkhard Madea, Isabella Moore, Jorg Morland, Siri H. Opdal, Petra Råsten-Almqvist, Martin Schlaud, Peter Sidebotham, Kari Skullerud, Gisela Stoltenburg-Didinger, Arne Stray-Pedersen, Lisbeth Sveum, Torleiv O. Rognum. (2007) Sudden infant death syndrome (SIDS)—Standardised investigations and classification: Recommendations. Forensic Science International 165:2-3, 129-143
CrossRef53
Peter J. Schwartz, Lia Crotti. (2007) Can a Message From the Dead Save Lives?. Journal of the American College of Cardiology 49:2, 247-249
CrossRef54
John M. Graham. 2007. Infant Sleeping Position and Sudden Infant Death Syndrome. , 157-159.
CrossRef55
Steven Karch. 2006. Toxicogenetics. , 1087-1115.
CrossRef56
Irene M. van Langen, Arthur A.M. Wilde. (2006) Newborn screening to prevent sudden cardiac death?. Heart Rhythm 3:11, 1356-1359
CrossRef57
Peter J. Schwartz. (2006) Newborn ECG screening to prevent sudden cardiac death. Heart Rhythm 3:11, 1353-1355
CrossRef58
J. Jay Gargus. 2006. Receptor, Transporter and Ion Channel Diseases. .
CrossRef59
G Millat, P Chevalier, L Restier-Miron, A Da Costa, P Bouvagnet, B Kugener, L Fayol, C Gonzàlez Armengod, B Oddou, V Chanavat, E Froidefond, R Perraudin, R Rousson, C Rodriguez-Lafrasse. (2006) Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome. Clinical Genetics 70:3, 214-227
CrossRef60
Brion S. Maher, Mary L. Marazita, Casey Rand, Lili Zhou, Elizabeth M. Berry-Kravis, Debra E. Weese-Mayer. (2006) 3′ UTR polymorphism of the serotonin transporter gene and sudden infant death syndrome: Haplotype analysis. American Journal of Medical Genetics Part A 140A:13, 1453-1457
CrossRef61
Horst Wedekind, Thomas Bajanowski, Patrick Friederich, Günter Breithardt, Thomas Wülfing, Cornelia Siebrands, Birgit Engeland, Gerold Mönnig, Wilhelm Haverkamp, Bernd Brinkmann, Eric Schulze-Bahr. (2006) Sudden infant death syndrome and long QT syndrome: an epidemiological and genetic study. International Journal of Legal Medicine 120:3, 129-137
CrossRef62
Carlo Napolitano, Raffaella Bloise, Silvia G. Priori. (2006) Gene-specific therapy for inherited arrhythmogenic diseases. Pharmacology & Therapeutics 110:1, 1-13
CrossRef63
S. Rasche, T. Koch, M. Hübler. (2006) Das Long-QT-Syndrom in der Anästhesie. Der Anaesthesist 55:3, 229-246
CrossRef64
M. R. ROSEN, I. S. COHEN. (2006) Molecular/genetic determinants of repolarization and their modification by environmental stress. Journal of Internal Medicine 259:1, 7-23
CrossRef65
ANDREA SARKOZY, PEDRO BRUGADA. (2005) Sudden Cardiac Death and Inherited Arrhythmia Syndromes. Journal of Cardiovascular Electrophysiology 16:s1, S8-S20
CrossRef66
Jiqing Guo, Shu Zhan, James P. Lees-Miller, GuoQi Teng, Henry J. Duff. (2005) Exaggerated block of hERG (KCNH2) and prolongation of action potential duration by erythromycin at temperatures between 37°C and 42°C. Heart Rhythm 2:8, 860-866
CrossRef67
Gertie C.M. Beaufort-Krol, Maarten P. van den Berg, Arthur A.M. Wilde, J. Peter van Tintelen, Jan Willem Viersma, Connie R. Bezzina, Margreet Th.E. Bink-Boelkens. (2005) Developmental Aspects of Long QT Syndrome Type 3 and Brugada Syndrome on the Basis of a Single SCN5A Mutation in Childhood. Journal of the American College of Cardiology 46:2, 331-337
CrossRef68
Stephanie J. Todd, M. Jay Campbell, Dan M. Roden, Prince J. Kannankeril. (2005) Novel Brugada SCN5A mutation causing sudden death in children. Heart Rhythm 2:5, 540-543
CrossRef69
Michael J. Ackerman. (2005) Cardiac Causes of Sudden Unexpected Death in Children and Their Relationship to Seizures and Syncope: Genetic Testing for Cardiac Electropathies. Seminars in Pediatric Neurology 12:1, 52-58
CrossRef70
G Michael Vincent, Li Zhang. (2005) The Role of Genotyping in Diagnosing Cardiac Channelopathies. Molecular Diagnosis 9:3, 105-118
CrossRef71
Michael J. Ackerman, Igor Splawski, Jonathan C. Makielski, David J. Tester, Melissa L. Will, Katherine W. Timothy, Mark T. Keating, Gregg Jones, Monica Chadha, Christopher R. Burrow, J. Claiborne Stephens, Chuanbo Xu, Richard Judson, Mark E. Curran. (2004) Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: Implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing. Heart Rhythm 1:5, 600-607
CrossRef72
DT Mage, EM Donner. (2004) The fifty percent male excess of infant respiratory mortality. Acta Paediatrica 93:9, 1210-1215
CrossRef73
Cristina Montomoli, Maria C. Monti, Marco Stramba-Badiale, Alessandra Marinoni, Nives Foglieni, Vittorio Carreri, Maurizio Amigoni, Peter J. Schwartz. (2004) Mortality due to sudden infant death syndrome in Northern Italy, 1990-2000: a baseline for the assessment of prevention campaigns. Paediatric and Perinatal Epidemiology 18:5, 336-343
CrossRef74
Sarah S. LeRoy, Mark Russell. (2004) Long QT Syndrome and Other Repolarization-related Dysrhythmias. AACN Clinical Issues: Advanced Practice in Acute and Critical Care 15:3, 419-431
CrossRef75
Cathy Head, Mark Gardiner. (2003) Paroxysms of excitement: sodium channel dysfunction in heart and brain. BioEssays 25:10, 981-993
CrossRef76
R. Samson, R. Berg, R. Bingham. (2003) Use of automated external defibrillators for children: an update.. Resuscitation 57:3, 237-243
CrossRef77
J. Jay Gargus. (2003) Unraveling Monogenic Channelopathies and Their Implications for Complex Polygenic Disease. The American Journal of Human Genetics 72:4, 785-803
CrossRef78
Mackenzi Mbai, Sridharan Rajamani, Brian P. Delisle, Blake D. Anson, Corey Anderson, Jonathan C. Makielski, Craig T. January. (2002) Genetic basis for the origin of cardiac arrhythmias: Implications for therapy. Current Cardiology Reports 4:5, 411-417
CrossRef79
R.F Byring, H Pihko, A Tsujino, X.-M Shen, B Gustafsson, P Hackman, K Ohno, A.G Engel, B Udd. (2002) Congenital myasthenic syndrome associated with episodic apnea and sudden infant death. Neuromuscular Disorders 12:6, 548-553
CrossRef80
Matteo Vatta, Robert Dumaine, Charles Antzelevitch, Ramon Brugada, Hua Li, Neil E. Bowles, Koonlawee Nademanee, Josep Brugada, Pedro Brugada, Jeffrey A. Towbin. (2002) Novel mutations in domain I of SCN5A cause Brugada syndrome. Molecular Genetics and Metabolism 75:4, 317-324
CrossRef81
Robert Dumaine, Charles Antzelevitch. (2002) Molecular mechanisms underlying the long QT syndrome. Current Opinion in Cardiology 17:1, 36-42
CrossRef82
Peter J Schwartz, Silvia G Priori, Raffaella Bloise, Carlo Napolitano, Elena Ronchetti, Andrea Piccinini, Carlo Goj, Günter Breithardt, Eric Schulze-Bahr, Horst Wedekind, Janni Nastoli. (2001) Molecular diagnosis in a child with sudden infant death syndrome. The Lancet 358:9290, 1342-1343
CrossRef83
N Zhao. (2001) Electrocardiographic changes during postnatal development in conscious swine with cardiac autonomic imbalance. Autonomic Neuroscience 88:3, 167-174
CrossRef84
(2000) Prolongation of the QT Interval and SIDS. New England Journal of Medicine 343:25, 1896-1897
Full Text85
Robert H. Haslam. (2000) Smoking and Sleep Position are only Pieces of the Puzzle Resulting in The Sudden Infant Death Syndrome. Pediatric Research 48:6, 715
CrossRef
