Romano-Ward syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vamsikrishna Gunnam M.B.B.S [2]

Synonyms and keywords: Autosomal dominant long QT syndrome; long QT syndrome without deafness; romano-ward long QT syndrome; ward-romano syndrome; romano-ward syndrome; LQTS; RWS

Overview

Romano-Ward syndrome is a rare congenital genetic condition with autosomal dominant inheritance pattern which leads to abnormal ventricular myocardial repolarization which results in long QT syndrome (LQTS). Among all other long QT syndrome (LQTS) Romano-Ward syndrome is the most common one. Romano-Ward syndrome is due to mutation in LQT1, LQT2 and LQT3 genes. Romano-Ward syndrome has a purely cardiac phenotype of QT prolongation in contrast to Jervell and Lange-Nielsen syndrome which has both sensorineural deafness and cardiac events.

Historical Perspective

Classification

  • LQT1-associated S3 mutants traffic to the plasma membrane in ltk− cells. (A) Western blot of WT and mutant KCNQ1+KCNE1 proteins expressed in ltk− cells, untreated and treated with proteinase K (PK) to distinguish surface-expressed channel from internal. After normalization to actin for control of loading, the percent surface protein was determined from the density of bands before and after proteinase K treatment (n = 3) and was found to be: WT, 73%; D202H, 91%; D202N, 80%; I204F, 80%; I204M, 90%; V205M, 75%; S209F, 82%; V215M, 75%. (B) Model of KCNQ1 tetrameric channels showing the locations of S3 mutations in space fill from the side and the extracellular face, with each subunit a different color. Case courtesy by Jodene Eldstrom et al[8]
    The Long QT syndrome (LQTS) may be classified into several subtypes:[9][10][11][12][13]


LQT Gene Involved Chromosome involved Protein Involved Ion channel Involved
LQT 1 KCNQ1 11p15.5 Iks a subunit Iks
LQT 2 HERG 7q35-36 Ikr a subunit Ikr
LQT 3 SCN5A 3q21-24 Sodium channel INa
LQT 4 NOT KNOWN 4q25-27 Unknown Unknown
LQT 5 KCNE1 21q22.1-2 Iks a subunit Iks
LQT 6 KCNE2 21q22.1 Ikr b subunit Ikr

Pathophysiology

Causes

Genetic Causes

Differentiating Romano-Ward syndrome from other Diseases

Romano-Ward syndrome must be differentiated from Jervell and Lange-Nielsen syndrome (JLNS), Timothy syndrome, Andersen-Tawil syndrome, Brugada syndrome, and Sudden infant death syndrome (SIDS).[20][21][22][23][24][25][26][27]

Epidemiology and Demographics

Incidence

  • The incidence of Romano-Ward syndrome is approximately 1 in 2,000 people worldwide individuals worldwide.

Prevalence

  • The prevalence of Romano-Ward syndrome is approximately 1:20 000 to 1:5000 individuals worldwide.[28]
  • The prevalence of Romano-Ward syndrome is approximately 1 in 2000 live births.

Race

  • There is no racial predilection to Romano-Ward syndrome.

Gender

  • Romano-Ward syndrome affects men and women equally.

Risk Factors

  • Apart from the genetic mutations in ANK2, KCNE1, KCNE2, KCNH2, KCNQ1, and SCN5A genes, there are some risk factors associated with Romano-Ward syndrome.
  • Other common risk factors in the development of Romano-Ward syndrome symptoms include sudden sleep arousal, exercise and intense or sudden emotion which include the following:[29][30]
    • Competitive sports, amusement park rides, frightening movies, jumping into cold water etc
  • Based on the genotype the triggering events may differ, for example:[31]
    • In patients with LQT1 genotype exercise or swimming is the trigger for cardiac events due to stimulation of vasovagal reflex
    • In patients with LQT2 genotype emotions, exposure to auditory stimuli like door bells, telephone ring can trigger the cardiac events
    • In patients with LQT3 genotype cardiac events can be triggered during sleep

Screening

  • There is insufficient evidence to recommend routine screening for Romano-Ward syndrome.

Natural History, Complications and Prognosis

Natural History

  • The symptoms of Romano-Ward syndrome usually develop in the second decade of life, and start with symptoms such as syncope and palpitations.
  • The symptoms of Romano-Ward syndrome typically decreases with increase in the age, after the age of 40 years the symptoms are less common than usual.

Complications

Prognosis

Diagnosis

Diagnostic study of choice

History and Symptoms

Common Symptoms

Common symptoms of Romano-Ward syndrome include:[33][34]

Less Common Symptoms

Less common symptoms of Romano-Ward syndrome include

Physical Examination

Vital Signs

Heart



Romano-Ward syndrome
LQT1 patient ECG showing a normal T wave pattern and average QTc of about more than 480 msec. Case courtesy by G. Michael Vincent, MD[35]

Laboratory Findings

  • There are no diagnostic laboratory findings associated with Romano-Ward syndrome.

Electrocardiogram

X-Ray

LQTS
Representative electrocardiograms (ECG) from members of a family with LQTS. Top, ECG from a normal family member (I-1); Middle, ECG from a heterozygous mutation carrier; Bottom, ECG from a homozygous mutation carrier.[44]
  • There are no x-ray findings associated with Romano-Ward syndrome.

Ultrasound

MRI

Treatment

Medical Therapy

Acute Management of Torsades de pointes

Interventions

Surgery

Primary Prevention

Secondary Prevention


Template:WikiDoc Sources

References

  1. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K; et al. (1993). "GeneReviews®". PMID 20301308.
  2. Ackerman MJ, Siu BL, Sturner WQ, Tester DJ, Valdivia CR, Makielski JC; et al. (2001). "Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome". JAMA. 286 (18): 2264–9. doi:10.1001/jama.286.18.2264. PMID 11710892.
  3. Arnestad M, Crotti L, Rognum TO, Insolia R, Pedrazzini M, Ferrandi C; et al. (2007). "Prevalence of long-QT syndrome gene variants in sudden infant death syndrome". Circulation. 115 (3): 361–7. doi:10.1161/CIRCULATIONAHA.106.658021. PMID 17210839.
  4. Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C; et al. (2001). "Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias". Circulation. 103 (1): 89–95. doi:10.1161/01.cir.103.1.89. PMID 11136691.
  5. Wedekind H, Bajanowski T, Friederich P, Breithardt G, Wülfing T, Siebrands C; et al. (2006). "Sudden infant death syndrome and long QT syndrome: an epidemiological and genetic study". Int J Legal Med. 120 (3): 129–37. doi:10.1007/s00414-005-0019-0. PMID 16012827.
  6. Juang JJ, Horie M (2016). "Genetics of Brugada syndrome". J Arrhythm. 32 (5): 418–425. doi:10.1016/j.joa.2016.07.012. PMC 5063259. PMID 27761167.
  7. Thomas D, Wimmer AB, Karle CA, Licka M, Alter M, Khalil M; et al. (2005). "Dominant-negative I(Ks) suppression by KCNQ1-deltaF339 potassium channels linked to Romano-Ward syndrome". Cardiovasc Res. 67 (3): 487–97. doi:10.1016/j.cardiores.2005.05.003. PMID 15950200.
  8. "Mechanistic basis for LQT1 caused by S3 mutations in the KCNQ1 subunit of IKs".
  9. Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M, Romey G (1996). "K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current". Nature. 384 (6604): 78–80. doi:10.1038/384078a0. PMID 8900282.
  10. Yamaguchi M, Shimizu M, Ino H, Terai H, Hayashi K, Mabuchi H; et al. (2003). "Clinical and electrophysiological characterization of a novel mutation (F193L) in the KCNQ1 gene associated with long QT syndrome". Clin Sci (Lond). 104 (4): 377–82. doi:10.1042/CS20020152. PMID 12653681.
  11. Vincent GM (2002) The long QT syndrome. Indian Pacing Electrophysiol J 2 (4):127-42. PMID: 16951729
  12. Itzhaki I, Maizels L, Huber I, Zwi-Dantsis L, Caspi O, Winterstern A; et al. (2011). "Modelling the long QT syndrome with induced pluripotent stem cells". Nature. 471 (7337): 225–9. doi:10.1038/nature09747. PMID 21240260.
  13. Vincent GM (1998). "The molecular genetics of the long QT syndrome: genes causing fainting and sudden death". Annu Rev Med. 49: 263–74. doi:10.1146/annurev.med.49.1.263. PMID 9509262.
  14. Lehnart SE, Ackerman MJ, Benson DW, Brugada R, Clancy CE, Donahue JK; et al. (2007). "Inherited arrhythmias: a National Heart, Lung, and Blood Institute and Office of Rare Diseases workshop consensus report about the diagnosis, phenotyping, molecular mechanisms, and therapeutic approaches for primary cardiomyopathies of gene mutations affecting ion channel function". Circulation. 116 (20): 2325–45. doi:10.1161/CIRCULATIONAHA.107.711689. PMID 17998470.
  15. Sanguinetti MC, Curran ME, Zou A, Shen J, Spector PS, Atkinson DL; et al. (1996). "Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel". Nature. 384 (6604): 80–3. doi:10.1038/384080a0. PMID 8900283.
  16. Arbour L, Rezazadeh S, Eldstrom J, Weget-Simms G, Rupps R, Dyer Z; et al. (2008). "A KCNQ1 V205M missense mutation causes a high rate of long QT syndrome in a First Nations community of northern British Columbia: a community-based approach to understanding the impact". Genet Med. 10 (7): 545–50. doi:10.1097GIM.0b013e31817c6b19 Check |doi= value (help). PMID 18580685.
  17. Yamaguchi M, Shimizu M, Ino H, Terai H, Hayashi K, Mabuchi H; et al. (2003). "Clinical and electrophysiological characterization of a novel mutation (F193L) in the KCNQ1 gene associated with long QT syndrome". Clin Sci (Lond). 104 (4): 377–82. doi:10.1042/CS20020152. PMID 12653681.
  18. Sanguinetti MC, Curran ME, Zou A, Shen J, Spector PS, Atkinson DL; et al. (1996). "Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel". Nature. 384 (6604): 80–3. doi:10.1038/384080a0. PMID 8900283.
  19. Napolitano C, Priori SG, Schwartz PJ, Bloise R, Ronchetti E, Nastoli J; et al. (2005). "Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice". JAMA. 294 (23): 2975–80. doi:10.1001/jama.294.23.2975. PMID 16414944.
  20. Thomas D, Wimmer AB, Karle CA, Licka M, Alter M, Khalil M; et al. (2005). "Dominant-negative I(Ks) suppression by KCNQ1-deltaF339 potassium channels linked to Romano-Ward syndrome". Cardiovasc Res. 67 (3): 487–97. doi:10.1016/j.cardiores.2005.05.003. PMID 15950200.
  21. Juang JJ, Horie M (2016). "Genetics of Brugada syndrome". J Arrhythm. 32 (5): 418–425. doi:10.1016/j.joa.2016.07.012. PMC 5063259. PMID 27761167.
  22. Tester DJ, Ackerman MJ (2009). "Cardiomyopathic and channelopathic causes of sudden unexplained death in infants and children". Annu Rev Med. 60: 69–84. doi:10.1146/annurev.med.60.052907.103838. PMID 18928334.
  23. Wedekind H, Bajanowski T, Friederich P, Breithardt G, Wülfing T, Siebrands C; et al. (2006). "Sudden infant death syndrome and long QT syndrome: an epidemiological and genetic study". Int J Legal Med. 120 (3): 129–37. doi:10.1007/s00414-005-0019-0. PMID 16012827.
  24. Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C; et al. (2001). "Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias". Circulation. 103 (1): 89–95. doi:10.1161/01.cir.103.1.89. PMID 11136691.
  25. Arnestad M, Crotti L, Rognum TO, Insolia R, Pedrazzini M, Ferrandi C; et al. (2007). "Prevalence of long-QT syndrome gene variants in sudden infant death syndrome". Circulation. 115 (3): 361–7. doi:10.1161/CIRCULATIONAHA.106.658021. PMID 17210839.
  26. Ackerman MJ, Siu BL, Sturner WQ, Tester DJ, Valdivia CR, Makielski JC; et al. (2001). "Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome". JAMA. 286 (18): 2264–9. doi:10.1001/jama.286.18.2264. PMID 11710892.
  27. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K; et al. (1993). "GeneReviews®". PMID 20301308.
  28. Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G; et al. (2009). "Prevalence of the congenital long-QT syndrome". Circulation. 120 (18): 1761–7. doi:10.1161/CIRCULATIONAHA.109.863209. PMC 2784143. PMID 19841298.
  29. Schwartz, Peter J.; Spazzolini, Carla; Crotti, Lia; Bathen, Jørn; Amlie, Jan P.; Timothy, Katherine; Shkolnikova, Maria; Berul, Charles I.; Bitner-Glindzicz, Maria; Toivonen, Lauri; Horie, Minoru; Schulze-Bahr, Eric; Denjoy, Isabelle (2006). "The Jervell and Lange-Nielsen Syndrome". Circulation. 113 (6): 783–790. doi:10.1161/CIRCULATIONAHA.105.592899. ISSN 0009-7322.
  30. Schwartz PJ, Spazzolini C, Crotti L, Bathen J, Amlie JP, Timothy K; et al. (2006). "The Jervell and Lange-Nielsen syndrome: natural history, molecular basis, and clinical outcome". Circulation. 113 (6): 783–90. doi:10.1161/CIRCULATIONAHA.105.592899. PMID 16461811.
  31. Vincent GM (1998). "The molecular genetics of the long QT syndrome: genes causing fainting and sudden death". Annu Rev Med. 49: 263–74. doi:10.1146/annurev.med.49.1.263. PMID 9509262.
  32. Tester DJ, Ackerman MJ (2009). "Cardiomyopathic and channelopathic causes of sudden unexplained death in infants and children". Annu Rev Med. 60: 69–84. doi:10.1146/annurev.med.60.052907.103838. PMID 18928334.
  33. Vincent GM (1998). "The molecular genetics of the long QT syndrome: genes causing fainting and sudden death". Annu Rev Med. 49: 263–74. doi:10.1146/annurev.med.49.1.263. PMID 9509262.
  34. Engelstein ED (2003). "Long QT syndrome: a preventable cause of sudden death in women". Curr Womens Health Rep. 3 (2): 126–34. PMID 12628082.
  35. "The long QT syndrome".
  36. Barsheshet A, Dotsenko O, Goldenberg I (2013). "Genotype-specific risk stratification and management of patients with long QT syndrome". Ann Noninvasive Electrocardiol. 18 (6): 499–509. doi:10.1111/anec.12117. PMID 24206565.
  37. "The Long QT Syndrome".
  38. Goldenberg I, Horr S, Moss AJ, Lopes CM, Barsheshet A, McNitt S; et al. (2011). "Risk for life-threatening cardiac events in patients with genotype-confirmed long-QT syndrome and normal-range corrected QT intervals". J Am Coll Cardiol. 57 (1): 51–9. doi:10.1016/j.jacc.2010.07.038. PMC 3332533. PMID 21185501.
  39. Goldenberg I, Moss AJ, Peterson DR, McNitt S, Zareba W, Andrews ML; et al. (2008). "Risk factors for aborted cardiac arrest and sudden cardiac death in children with the congenital long-QT syndrome". Circulation. 117 (17): 2184–91. doi:10.1161/CIRCULATIONAHA.107.701243. PMC 3944375. PMID 18427136.
  40. Vincent GM (1998). "The molecular genetics of the long QT syndrome: genes causing fainting and sudden death". Annu Rev Med. 49: 263–74. doi:10.1146/annurev.med.49.1.263. PMID 9509262.
  41. Hobbs, Jenny B.; Peterson, Derick R.; Moss, Arthur J.; McNitt, Scott; Zareba, Wojciech; Goldenberg, Ilan; Qi, Ming; Robinson, Jennifer L.; Sauer, Andrew J.; Ackerman, Michael J.; Benhorin, Jesaia; Kaufman, Elizabeth S.; Locati, Emanuela H.; Napolitano, Carlo; Priori, Silvia G.; Towbin, Jeffrey A.; Vincent, G. Michael; Zhang, Li (2006). "Risk of Aborted Cardiac Arrest or Sudden Cardiac Death During Adolescence in the Long-QT Syndrome". JAMA. 296 (10): 1249. doi:10.1001/jama.296.10.1249. ISSN 0098-7484.
  42. Friedrichs S, Malan D, Sasse P (2013). "Modeling long QT syndromes using induced pluripotent stem cells: current progress and future challenges". Trends Cardiovasc Med. 23 (4): 91–8. doi:10.1016/j.tcm.2012.09.006. PMID 23266156.
  43. Hofman N, Wilde AA, Kääb S, van Langen IM, Tanck MW, Mannens MM; et al. (2007). "Diagnostic criteria for congenital long QT syndrome in the era of molecular genetics: do we need a scoring system?". Eur Heart J. 28 (5): 575–80. doi:10.1093/eurheartj/ehl355. PMID 17090615.
  44. "Identification of a novel KCNQ1 mutation associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long QT syndrome in a Chinese family".
  45. "Familial long QT syndrome and late development of dilated cardiomyopathy in a child with a KCNQ1 mutation: A case report".
  46. Tester DJ, Ackerman MJ (2009). "Cardiomyopathic and channelopathic causes of sudden unexplained death in infants and children". Annu Rev Med. 60: 69–84. doi:10.1146/annurev.med.60.052907.103838. PMID 18928334.
  47. Tester DJ, Ackerman MJ (2009). "Cardiomyopathic and channelopathic causes of sudden unexplained death in infants and children". Annu Rev Med. 60: 69–84. doi:10.1146/annurev.med.60.052907.103838. PMID 18928334.
  48. Vincent GM, Schwartz PJ, Denjoy I, Swan H, Bithell C, Spazzolini C; et al. (2009). "High efficacy of beta-blockers in long-QT syndrome type 1: contribution of noncompliance and QT-prolonging drugs to the occurrence of beta-blocker treatment "failures"". Circulation. 119 (2): 215–21. doi:10.1161/CIRCULATIONAHA.108.772533. PMID 19118258.
  49. Goldenberg I, Bradley J, Moss A, McNitt S, Polonsky S, Robinson JL; et al. (2010). "Beta-blocker efficacy in high-risk patients with the congenital long-QT syndrome types 1 and 2: implications for patient management". J Cardiovasc Electrophysiol. 21 (8): 893–901. doi:10.1111/j.1540-8167.2010.01737.x. PMC 4005824. PMID 20233272.
  50. Abu-Zeitone A, Peterson DR, Polonsky B, McNitt S, Moss AJ (2014). "Efficacy of different beta-blockers in the treatment of long QT syndrome". J Am Coll Cardiol. 64 (13): 1352–8. doi:10.1016/j.jacc.2014.05.068. PMID 25257637.
  51. Chockalingam P, Crotti L, Girardengo G, Johnson JN, Harris KM, van der Heijden JF; et al. (2012). "Not all beta-blockers are equal in the management of long QT syndrome types 1 and 2: higher recurrence of events under metoprolol". J Am Coll Cardiol. 60 (20): 2092–9. doi:10.1016/j.jacc.2012.07.046. PMC 3515779. PMID 23083782.
  52. Ahn J, Kim HJ, Choi JI, Lee KN, Shim J, Ahn HS; et al. (2017). "Effectiveness of beta-blockers depending on the genotype of congenital long-QT syndrome: A meta-analysis". PLoS One. 12 (10): e0185680. doi:10.1371/journal.pone.0185680. PMC 5653191. PMID 29059199.
  53. Barsheshet A, Dotsenko O, Goldenberg I (2013). "Genotype-specific risk stratification and management of patients with long QT syndrome". Ann Noninvasive Electrocardiol. 18 (6): 499–509. doi:10.1111/anec.12117. PMID 24206565.
  54. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K; et al. (1993). "GeneReviews®". PMID 20301579.
  55. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K; et al. (1993). "GeneReviews®". PMID 20301579.