Romano–Ward syndrome (RWS) is the most common form of congenital 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.
|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|
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 increases the risk of abnormal heart rhythms or arrhythmias. These are typically a form of ventricular tachycardia known as Torsades de Pointes which can cause faints, seizures, or even sudden death. Less dangerous arrhythmias such as atrial fibrillation also occur, causing symptoms of heart racing or palpitations. However, many of those with Romano–Ward syndrome will remain free from arrhythmias and therefore free from symptoms. Certain situations are more likely to precipitate arrhythmias such as exercise or mental stress in the LQT1 subtype, sudden loud noise in the LQT2 subtype, and during sleep or immediately upon waking in the LQT3 subtype.
Romano–Ward syndrome can be differentiated from other forms of long QT syndrome by Romano-Ward's sole involvement of the heart. While other forms of long QT syndrome are associated with deafness (Jervell and Lange-Nielsen syndrome), intermittent weakness and bone abormailities (LQT7, Andersen-Tawil syndrome), and autism spectrum disorder (LQT8, Timothy syndrome), these extra-cardiac manifestations are not seen in Romano-Ward.
Romano–Ward syndrome is a descriptive term for a group of subtypes of long QT syndrome, specifically subtypes LQT1-6 and LQT9-16. Several subtypes of Romano–Ward syndrome have been described based on the underlying genetic variant. These subtypes differ in clinical presentation and their response to treatment. There is robust evidence that the genetic variants associated with the three most common subtypes (LQT1, LQT2 and LQT3) are truly causative of the syndrome. However, there is uncertainty as to whether some of the other rarer subtypes are truly disease-causing by themselves or instead make individuals more susceptible to QT prolongation in response to other factors such as medication or low blood potassium levels (hypokalaemia).
LQT1 is the most common subtype of Romano–Ward syndrome, responsible for 30 to 35% of all cases. The gene responsible, KCNQ1, has been isolated to chromosome 11p15.5 and encodes the alpha subunit of the KvLQT1 potassium channel. This subunit interacts with other proteins (in particular, the minK beta subunit) to create the channel, which carries the delayed potassium rectifier current IKs responsible for the repolarisation phase of the cardiac action potential.
Variants in KCNQ1 cause the LQT1 subtype of Romano–Ward syndrome when a single copy of the variant is inherited (heterozygous, autosomal dominant inheritance). When two copies of the variant are inherited (homozygous, autosomal recessive inheritance) the more severe Jervell and Lange-Nielsen syndrome is found, associated with more marked QT prolongation, congenital sensorineural deafness, and a greater risk of arrhythmias.
LQT1 is associated with a high risk of faints but lower risk of sudden death than LQT2.
LQT1 may also affect glucose regulation. After ingesting glucose, those with LQT1 produce more insulin than would be expected, which is followed by a period of insulin resistance. When the resistance diminishes, abnormally low blood glucose levels (hypoglycaemia) are sometimes seen.
The LQT2 subtype is the second-most common form of Romano–Ward syndrome, responsible for 25 to 30% of all cases. This form of Romano–Ward syndrome is caused by variants in the KCNH2 gene on chromosome 7. KCNH2 (also known as hERG) encodes the potassium channel which carries the rapid inward rectifier current IKr. This current contributes to the terminal repolarisation phase of the cardiac action potential, and therefore the length of the QT interval.
The LQT3 subtype of Romano–Ward syndrome is caused by variants in the SCN5A gene located on chromosome 3p21-24. SCN5A encodes the alpha subunit of the cardiac sodium channel, NaV1.5, responsible for the sodium current INa which depolarises cardiac cells at the start of the action potential. Cardiac sodium channels normally inactivate rapidly, but the mutations involved in LQT3 slow their inactivation leading to a small sustained 'late' sodium current. This continued inward current prolongs the action potential and thereby the QT interval.
A large number of mutations have been characterized as leading to or predisposing to LQT3. Calcium has been suggested as a regulator of SCN5A protein, and the effects of calcium on SCN5A may begin to explain the mechanism by which some these mutations cause LQT3. Furthermore, mutations in SCN5A can cause Brugada syndrome, cardiac conduction disease, and dilated cardiomyopathy. In rare situations, some affected individuals can have combinations of these diseases.
LQT5 is caused by variants in the KCNE1 gene. This gene is responsible for the potassium channel beta subunit MinK which, in conjunction with the alpha subunit encoded by KCNQ1, is responsible for the potassium current IKs, and variants associated with prolonged QT intervals decrease this current. The same variants in KCNE1 can cause the more severe Jervell and Lange-Nielsen syndrome when two copies are inherited (homozygous inheritance) and the milder LQT5 subtype of Romano–Ward syndrome when a single copy of the variant is inherited (heterozygous inheritance).
The LQT6 subtype is caused by variants in the KCNE2 gene. This gene is responsible for the potassium channel beta subunit MiRP1 which generates the potassium current IKr, and variant that decrease this current have been associated with prolongation of the QT interval. However, subsequent evidence such as the relatively common finding of variants in the gene in those without long QT syndrome, and the general need for a second stressor such as hypokalaemia to be present to reveal the QT prolongation, has suggested that this gene instead represents a modifier to susceptibility to QT prolongation. Some therefore dispute whether variants in the gene are sufficient to cause Romano–Ward syndrome by themselves.
LQT9 is caused by variants in the membrane structural protein, caveolin-3. Caveolins form specific membrane domains called caveolae in which voltage-gated sodium channels sit. Similar to LQT3, these caveolin variants increase the late sustained sodium current, which impairs cellular repolarization.
LQT10 is an extremely rare subtype, caused by variants in the SCN4B gene. The product of this gene is an auxiliary beta-subunit (NaVβ4) forming cardiac sodium channels, variants in which increase the late sustained sodium current. LQT13 is caused by variants in GIRK4, a protein involved in the parasympathetic modulation of the heart. Clinically, the patients are characterized by only modest QT prolongation, but an increased propensity for atrial arrhythmias. LQT14, LQT15 and LQT16 are caused by variants in the genes responsible for calmodulin (CALM1, CALM2, and CALM3 respectively). Calmodulin interacts with several ion channels and its roles include modulation of the L-type calcium current in response to calcium concentrations, and trafficking the proteins produced by KCNQ1 and thereby influencing potassium currents. The precise mechanisms by which means these genetic variants prolong the QT interval remain uncertain.
Table of causative genes
|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).|
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.
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)
Romano–Ward syndrome is the most common form of inherited long QT syndrome, affecting an estimated 1 in 7,000 people worldwide.
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