Romano–Ward syndrome is the most common form of congenital Long QT syndrome (LQTS), a genetic heart condition that affects the electrical properties of heart muscle cells. Those affected are 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 inherited LQTS as it affects only the electrical properties of the heart, while other forms of LQTS can also affect other parts of the body.
Romano–Ward syndrome is caused by abnormal variants in the genes responsible for producing certain proteins used to transport charged particles (ion channels) within the heart. These abnormalities interfere with the electrical signals that heart cells use to coordinate contractions, causing the heart to take longer to recharge in between beats. The condition is usually diagnosed using an electrocardiogram, but other tests sometimes used include Holter monitoring, exercise testing, and genetic testing. It may be treated using medications such as beta-blockers, an implantable cardioverter-defibrillator, or surgery to disrupt the sympathetic nervous system. Romano–Ward syndrome is estimated to affect 1 in every 7,000 people.
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.
Causes
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
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). Loss-of-function mutations, commonly found in the voltage-sensing domain of the protein, often result in impaired trafficking to the cell surface at levels significantly lower than wild-type. These mutations have also been demonstrated to have a dominant-negative effect on wild-type protein trafficking, meaning that wild-type surface expression is impaired due to the existence of the non-functional protein. 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.