Romano–Ward syndrome

Romano–Ward syndrome
Schematic representation of normal ECG trace (sinus rhythm), with waves, segments, and intervals labeled.
Causes	Mutations in the KCNQ1, KCNH2, and SCN5A genes
Diagnostic method	EKG, Exercise test
Treatment	Beta-adrenergic blockade

Romano–Ward syndrome is the most common subtype of Long QT syndrome, a genetic heart condition that affects the electrical properties of heart muscle cells. The condition makes those affected at risk of abnormal heart rhythms which can lead to fainting, seizures, or sudden death.

Romano-Ward syndrome can be distinguished clinically from other forms of Long QT by affecting only the electrical properties of the heart, while other forms of long QT can also affect other parts of the body. The condition may be treated using medication such as beta-blockers, an implantable cardioverter-defibrillator, or surgery to disrupt the sympathetic nervous system.

Signs and symptoms

Romano–Ward syndrome presents the following in an affected individual:

• Ventricular fibrillation
• Syncope
• Torsade de pointes
• Abnormality of ear

Genetics

Romano–Ward syndrome is a descriptive term for a group of subtypes of long QT syndrome, specifically subtypes LQT1-6 and LQT9-16. These subtypes are characterised by autosomal dominant inheritance and only affect the electrical activity of the heart. Other forms of Long QT include Jervell-Lange-Nielsen syndrome, characterised by autosomal recessive inheritance and congenital deafness, Anderson-Tawil syndrome (LQT7) which combines a prolonged QT interval with periodic paralysis and an abnormally shaped face, and Timothy syndrome (LQT8) which combines a prolonged QT interval, abnormalities in the structure of the heart, and autism-spectrum disorder.

Type	OMIM	Gene	Notes
LQT1	192500	KCNQ1	Encodes the α-subunit of the slow delayed rectifier potassium channel KV7.1 carrying the potassium current IKs.
LQT2	152427	KCNH2	Also known as hERG. Encodes the α-subunit of the rapid delayed rectifier potassium channel KV11.1 carrying the potassium current IKr.
LQT3	603830	SCN5A	Encodes the e α-subunit of the cardiac sodium channel NaV1.5 carrying the sodium current INa.
LQT4	600919	ANK2	Encodes Ankyrin B which anchors the ion channels in the cell.  Disputed true association with QT prolongation.
LQT5	176261	KCNE1	Encodes MinK, a potassium channel β-subunit.
LQT6	603796	KCNE2	Encodes MiRP1, a potassium channel β-subunit.
LQT9	611818	CAV3	Encodes Caveolin-3 responsible for forming membrane pouches known as caveolae. Mutations in this gene may increase the late sodium INa.
LQT10	611819	SCN4B	Encodes the β4-subunit of the cardiac sodium channel.
LQT11	611820	AKAP9	Encode A-kinase associated protein which interacts with KV7.1.
LQT12	601017	SNTA1	Encodes syntrophin-α1.  Mutations in this gene may increase the late sodium current INa.
LQT13	600734	KCNJ5	Also known as GIRK4, encodes G protein-sensitive inwardly rectifying potassium channels (Kir3.4) which carry the potassium current IK(ACh).
LQT14	616247	CALM1	Encodes calmodulin-1, a calcium-binding messenger protein that interacts with the calcium current ICa(L).
LQT15	616249	CALM2	Encodes calmodulin-2, a calcium-binding messenger protein that interacts with the calcium current  ICa(L).
LQT16	114183	CALM3	Encodes calmodulin-3, a calcium-binding messenger protein that interacts with the calcium current ICa(L).

Mechanism

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KCNE2

In the Romano-Ward forms of Long QT syndrome, genetic mutations affect how positively-charged ions, such as potassium, sodium and calcium ions are transported in and out of heart cells. Many of these genes encode proteins which form or interact with ion channels. 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 heart beats, leading to abnormal heart rhythm characteristic of the syndrome.

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.

Diagnosis

In terms of the diagnosis of Romano–Ward syndrome the following is done to ascertain the condition (the Schwartz Score helps in so doing):

• Exercise test
• ECG
• Family history

Treatment

Propranolol

Treatment for Romano–Ward syndrome can deal with the imbalance between the right and left sides of the sympathetic nervous system which may play a role in the cause of this syndrome. The imbalance can be temporarily abolished with a left stellate ganglion block, which shorten the QT interval. If this is successful, surgical ganglionectomy can be performed as a permanent treatment.Ventricular dysrhythmia may be managed by beta-adrenergic blockade (propranolol)

Epidemiology

Romano-Ward syndrome is the most common form of inherited long QT syndrome, affecting an estimated 1 in 7,000 people worldwide.

See also

• Long QT syndrome
• Jervell and Lange-Nielsen syndrome
• Andersen-Tawil syndrome
• Timothy syndrome

Further reading

• Kelly, Evelyn B. (2013-01-07). Encyclopedia of Human Genetics and Disease. ABC-CLIO. ISBN 9780313387135. retrieved 2017-04-07
• Nakano, Yukiko; Shimizu, Wataru (2016-01-01). "Genetics of long-QT syndrome". Journal of Human Genetics. 61 (1): 51–55. doi:10.1038/jhg.2015.74. ISSN 1434-5161. PMID 26108145.

External links

Classification	D ICD-10: I45.8 ICD-9-CM: 794.31 OMIM: 192500 MeSH: D029597 DiseasesDB: 11661
External resources	Orphanet: 101016