Romano-Ward syndrome
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Synonyms and keywords: Autosomal Dominant Long QT syndrome, Long QT syndrome without deafness, LQTS, Romano-Ward Long QT syndrome, RWS, Ward-Romano syndrome, Romano-Ward syndrome
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
- In 1963, Romano and in 1964, Ward was the first to discover almost similar condition like Jervell and Lange-Nielsen syndrome and they named it as Romano-Ward syndrome.[1][2][3][4][5][6][7]
Classification
| 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
- Mutations in the ANK2, KCNE1, KCNE2, KCNH2, KCNQ1, and SCN5A genes cause Romano-Ward syndrome
- The proteins made by most of these genes form channels that transport positively-charged ions, such as potassium and sodium, in and out of cells
- In cardiac muscle, these potassium and sodium ion channels play critical roles in maintaining the heart's normal rhythm
- Mutations in any of these genes alter the structure or function of channels, which changes the flow of ions between cells and results in abnormal heart rhythm
- A disruption in ion transport alters the way the heartbeats, leading to the abnormal heart rhythm characteristic of Romano-Ward syndrome
- Unlike most genes involved in Romano-Ward syndrome, the ANK2 gene does not produce an ion channel but instead the protein made by the ANK2 gene ensures that other proteins, particularly ion channels, are inserted into the cell membrane appropriately
- Then the truncated protein results in impairing potassium channel function, which is known to result in long QT syndrome.
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).
Epidemiology and Demographics
Incidence
- The incidence/prevalence of [disease name] is approximately [number range] per 100,000 individuals worldwide.
- In [year], the incidence/prevalence of [disease name] was estimated to be [number range] cases per 100,000 individuals worldwide.
Prevalence
- The prevalence of Romano-Ward syndrome is approximately 1:20 000 to 1:5000 individuals worldwide.[10]
- The prevalence of Romano-Ward syndrome is approximately 1 in 2000 live births.
Age
- Patients of all age groups may develop [disease name].
- The incidence of [disease name] increases with age; the median age at diagnosis is [#] years.
- [Disease name] commonly affects individuals younger than/older than [number of years] years of age.
- [Chronic disease name] is usually first diagnosed among [age group].
- [Acute disease name] commonly affects [age group].
Race
- There is no racial predilection to [disease name].
- [Disease name] usually affects individuals of the [race 1] race. [Race 2] individuals are less likely to develop [disease name].
Gender
- [Disease name] affects men and women equally.
- [Gender 1] are more commonly affected by [disease name] than [gender 2]. The [gender 1] to [gender 2] ratio is approximately [number > 1] to 1.
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Inheritance
Causes
Mutations in the ANK2, KCNE1, KCNE2, KCNH2, KCNQ1, and SCN5A genes cause Romano-Ward syndrome. The proteins made by most of these genes form channels that transport positively-charged ions, such as potassium and sodium, in and out of cells.
In cardiac muscle, these ion channels play critical roles in maintaining the heart's normal rhythm. Mutations in any of these genes alter the structure or function of channels, which changes the flow of ions between cells.
A disruption in ion transport alters the way the heartbeats, leading to the abnormal heart rhythm characteristic of Romano-Ward syndrome.
Unlike most genes related to Romano-Ward syndrome, the ANK2 gene does not produce an ion channel. The protein made by the ANK2 gene ensures that other proteins, particularly ion channels, are inserted into the cell membrane appropriately.
A mutation in the ANK2 gene likely alters the flow of ions between cells in the heart, which disrupts the heart's normal rhythm and results in the features of Romano-Ward syndrome.
References
- ↑ Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K; et al. (1993). "GeneReviews®". PMID 20301308.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Vincent GM (2002) The long QT syndrome. Indian Pacing Electrophysiol J 2 (4):127-42. PMID: 16951729
- ↑ 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.