Romano-Ward syndrome is an inherited heart (cardiac) disorder characterized by abnormalities affecting the electrical system of the heart. The severity of Romano-Ward syndrome varies greatly from case to case. Some individuals may have no apparent symptoms (asymptomatic); others may develop abnormally increased heartbeats (tachyarrhythmias) resulting in episodes of unconsciousness (syncope), cardiac arrest, and potentially sudden death. Romano-Ward syndrome is inherited as an autosomal dominant trait.
In many cases, the first symptom of Romano-Ward syndrome is partial or total loss of consciousness (syncope) accompanied by abnormally fast heart rhythms known as polymorphic ventricular tachycardia (VT) or torsade de pointes (TdPs). TdPs may progress to a more serious condition known as ventricular fibrillation (VF) in which the heart’s normal electrical activity becomes disordered resulting in uncoordinated heartbeats and malfunction of the main pumping chambers of the heart (ventricles). Consequently, little or no blood is pumped from the heart. Ventricular fibrillation potentially results in cardiac arrest or sudden death.
Symptoms of Romano-Ward syndrome such as syncope tend to occur without warning and to recur unexpectedly. Overexertion, excitement or stress may trigger these recurrent symptoms, although they often begin without any precipitating factors. In some cases, episodes may be triggered by “startle” events such as an alarm clock going off or the phone ringing in the middle of the night. In some cases, events occur while the affected person is swimming. The severity and frequency of attacks vary. Some people may have mild chest pain with no loss of consciousness; others may lose consciousness completely or have grand mal seizures followed by a period of disorientation. In some cases, seizures may be the first apparent symptom of Romano-Ward syndrome. The severity and frequency of episodes often decrease during middle age.
Additional symptoms have occurred in some individuals with Romano-Ward syndrome including webbing of the fingers or toes (syndactyly), asthma, and diabetes mellitus.
Romano-Ward syndrome is inherited as an autosomal dominant trait. In rare cases, Romano-Ward syndrome occurs randomly as the result of a spontaneous genetic change (i.e., new mutation). These mutations are then passed on (inherited) as an autosomal dominant trait.
Genetic diseases are determined by two genes, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Romano-Ward syndrome has been shown to be caused by disruptions or changes (mutations) in one of at least six different genes: KCNQ1, KCNH2 (HERG; LQT2), SCN5A (LQT3), KCNE1 (LQT1), (LQT5; mink), KCNE2 (LQT6; MiRP1). Recently, the LQT4 gene was identified as ankyrin B. These genes produce (encode) specific protein structures (ion channels) found in heart cells. Ion channels regulate the movement of electrically charged particles (e.g., potassium and sodium ions) across heart cell membranes. These ions transmit electrical signals needed for normal function of the heart. Mutations of these genes result in abnormal function of the ion channels and, in turn, improper function of the heart’s electrical system. More than 200 different mutations of the seven identified genes have been reported.
Investigators have determined that the KCNQ1 (LQT1, previously called KvLQT1) gene is located on the short arm (p) of chromosome 11 (11p15.5). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p15.5″ refers to band 15 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The KCNH2 gene is located on the long arm (q) of chromosome 7 (7q35-q36. The SCN5A gene is located on the short arm of chromosome 3 (3p21). The KCNE1 gene is located on the long arm of chromosome 21 (21q22.1-q22.2). The KCNE2 gene is located on the long arm of chromosome 21 (21q22.1), while ankyrin B is localized. Mutations of an unidentified gene are located on chromosome 4 (4q).
Romano-Ward syndrome is characterized by an abnormal electrocardiogram that demonstrates a prolonged QT interval and abnormal T wave morphology. The functioning of the heart is controlled by electrical nerve impulses that regulate normal rhythmic pumping activity of the heart muscle. After each heartbeat, this electrical system recharges, a process known as repolarization. During electrical stimulation, the heart muscle contracts, a process known as depolarization. The QT interval measures the amount of time required for these two processes to occur. When the QT interval is longer than normal (prolonged), the heartbeat may become irregular. Hence, this is a disease of repolarization.
Romano-Ward syndrome affects males and females in equal numbers. The disorder is estimated to occur in 1 in 10,000 live births. However, because cases of Romano-Ward syndrome often go unrecognized, the disorder is under-diagnosed, making it difficult to determine its true frequency in the general population.
Symptoms of Romano-Ward syndrome usually become apparent during childhood, but may occur at any age.
A diagnosis of Romano-Ward syndrome is made based upon a thorough clinical evaluation, a detailed patient history and a specialized test called an electrocardiogram (ECG or EKG). Individuals with unexplained history of fainting, syncope or sudden cardiac arrest should be evaluated for Romano-Ward syndrome. An electrocardiogram records the heart's electrical impulses and may reveal abnormal electrical patterns such as a prolonged QT interval characteristic of individuals with Romano-Ward syndrome. In some cases, blood samples can be tested for the presence of specific genetic mutations. However, this testing is not clinically available at present.
The absence of congenital deafness differentiates Romano-Ward syndrome from Jervell and Lange-Nielsen syndrome. Family members of individuals with Romano-Ward syndrome should be tested symptoms (e.g., prolonged QT interval) characteristic of the disorder.
The treatment of individuals with Romano-Ward syndrome is aimed at preventing characteristic symptoms such as loss of consciousness or cardiac arrest. Specific medications, avoidance of triggering events, and certain medical devices may all be used to treat individuals with Romano-Ward syndrome.
The treatment of choice for most individuals with Romano-Ward syndrome is drug therapy with beta-adrenergic blocking agents (beta blockers). Beta blockers, which include propranolol, atenolol, and nadolol, reduce the workload of the heart by decreasing the electrical stimulation of the heart. Children and adults with Romano-Ward syndrome who do not have any apparent symptoms (asymptomatic) may receive preventative (prophylactic) treatment with beta blockers.
Individuals for whom beta blockers are unsuccessful may be treated by a surgical procedure in which certain nerves going to the heart are removed (left cardiac sympathetic denervation or sympathectomy). However, recently treatment with an implantable automatic cardioverter-defibrillator (ICD) has replaced sympathectomy as the treatment of choice in these individuals. This device detects the abnormal heartbeat automatically and selectively delivers an electrical impulse to the heart. ICDs are used in conjunction with antiarrythmic drug therapy.
Some individuals with Romano-Ward syndrome are encouraged to avoid potential triggering events such as jumping into cold water, amusement park rides or competitive sports. Genetic counseling may be of benefit for affected individuals and their families. Other treatments are symptomatic and supportive.
An implantable device, the QT-sensitive cybernetic pacemaker, is also being tested for individuals with high-risk Romano-Ward syndrome. This unit may be able to monitor heart rhythm and detect development of severe heart beat irregularities. Effectiveness and side effects of these implanted devices have not been fully documented and more extensive research is being pursued before their therapeutic value for Romano-Ward syndrome can be evaluated.
Drugs that block the effects of sodium channels (e.g., mexilitine, lidocaine, and flecainide) are being tested in individuals with the LQT3 (SCN5A mutations) form of Romano-Ward syndrome. Drugs that increase serum potassium are also being studied in those with mutations in potassium channel genes (KCNQ1, KCNH2). More research is necessary to determine the long-term safety and effectiveness of these potential treatments for individuals with Romano-Ward syndrome.
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