January 27, 2017
Years published: 1987, 1988, 1989, 1995, 1996, 2003, 2017
NORD gratefully acknowledges Robyn Hylind, MS, CGC, and Lauren Westgate, NP, Inherited Cardiac Arrhythmia Program, Boston Children’s Hospital, for assistance in the preparation of this report.
Long QT syndrome (LQTS) is an autosomal dominant disorder, caused by abnormalities of the heart’s electrical conduction system, and is characterized on the electrocardiogram (a test that records the electrical activity of the heart) by prolongation of the QT interval that corresponds to prolongation of the recovery phase or repolarization of the heart muscle (ventricular myocardium) after each heartbeat. QT prolongation predisposes those affected to an increased risk of life threatening sudden alterations in the cardiac rhythm, (termed arrhythmias), specifically torsade de pointes (TdP) or ventricular fibrillation (VF). These arrhythmias can lead to sudden loss of consciousness (syncope), cardiac arrest and potentially cause sudden cardiac death. The severity of cardiac symptoms varies greatly from one person to another, even among family members who carry the same rare genetic variant. Some individuals may have no apparent symptoms (asymptomatic) for their entire lives, whilst others develop arrhythmias resulting in episodes of syncope, and cardiac arrest, at a young age. Several different factors are known to trigger the onset of symptoms including physical activity, excitement and fright, although cardiac events may occur while asleep or at rest.
Long QT syndrome is caused by a disease-causing change (mutation) in one of at least 15 different genes that encode specific ion channels within the cardiomyocyte (heart muscle cell) membranes. These mutations are typically inherited in an autosomal dominant manner, although compound heterozygous (two mutations within one gene), digenic (mutations within two different genes) and homozygous (the same mutation in both copies of a single gene) alleles are all well recognized causes of Long QT syndrome. Individuals with more than one mutation typically have more severe symptoms than those with a single mutation.
In 1957, Jervell and Lange-Nielsen described a Norwegian family with 4 of 6 siblings affected by sensorineural deafness, significant QT prolongation and recurrent syncope starting in early childhood, resulting in the sudden death of 3 of the children (1). Subsequent descriptions of an almost identical condition aside from normal hearing were made in 1963 by Romano (2) and 1964 by Ward (3), who described multiple individuals from two distinct families affected by recurrent ventricular fibrillation, a condition 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). Ventricular fibrillation can lead to loss of consciousness during exertion (exertional syncope) and sudden death. All cases were typified by marked QT prolongation of the surface ECG. These two previously eponymous syndromes (the dominantly inherited Romano Ward and the recessive Jervell Lange-Nielsen) are now recognized as a single clinical entity, long QT syndrome (LQTS)
There are three major types of LTQS; namely LQTS 1, 2 and 3 which correspond to the first three genes and associated proteins (cardiac potassium and sodium channels) identified in the 1990s. Since then a number of other genes have been implicated, perhaps most notably those associated with calcium handling, although the three initial types remain the most prevalent and best characterized. Two syndromic LQT variants with varying extracardiac features, previously referred to as long QT 7 and long QT 8, are now referred to as Andersen-Tawil and Timothy syndromes respectively. NORD has individuals reports on these two disorders.
Symptoms, including syncope, can occur at any age from the newborn period to middle age, but most often appear during the pre-teen years through the 20s. Generally, the severity and frequency of episodes decreases during middle age and symptoms are less common after the age of 40 years. Approximately 50% of individuals, who have a mutation in one of the 15 genes that predispose to the disorder, ultimately develop symptoms; the others remain asymptomatic.
Symptoms include palpitations, presyncope and syncope, all of which relate to the onset of a specific ventricular arrhythmia (tachycardia), torsade de pointes. This is usually self-limiting and will self-terminate in approximately 80% of cases, which explains the recurrent nature of symptoms. However, this may persist leading to ventricular fibrillation with associated cardiac arrest that is fatal unless the patient is treated with a defibrillator to restore normal sinus rhythm. Tragically the first manifestation of LQTS can be fatal.
Symptoms, such as syncope, may occur without warning and recur unexpectedly. Exertion, excitement or stress may trigger these recurrent symptoms, although they often begin without any precipitating factors. Specific triggers are well recognized and are classically associated with specific subtypes. For example, exercise, especially swimming in LQTS1; exercise, emotional situations, and surprise or sudden noises, particularly when at rest (e.g. alarm clock or phone ringing), in LQTS2; and rest or sleep in LQTS3.
Another important trigger for cardiac events is medication. A significant number of prescribed agents which can be found at (www.crediblemeds.org) can affect potassium channel function and thereby further prolong the QT interval. It is important to differentiate between medications unmasking LQTS and true drug-induced QT prolongation, although the latter may also have a genetic basis.
Due to cerebral anoxia (i.e. lack of oxygen delivered to the brain during LQT associated arrhythmia), cardiac events may be mistaken for seizures. The misdiagnosis of LQTS as epilepsy is very well recognized. Therefore, patients with recurrent ‘seizures’ with normal neurological investigations and no response to anti-epileptic medication should have a comprehensive cardiac evaluation. Interestingly an overlap between LQTS and true epileptic seizures is recognized in a small proportion of patients with long QT2.
The severity and frequency of cardiac events varies depending on numerous individual factors, but specifically the QT interval, age, sex and LQT type. Ultimately, the QT interval is the best assessment of risk, and patients with severe QT prolongation often present in early childhood with symptomatic arrhythmias. The risk of cardiac events differs between males and females. Males appear to be at greater risk during childhood through puberty, often associated with long QT1. Females with long QT2 have an increased risk relative to males after puberty, after childbirth (postpartum) and after the menopause. The hormonal influences on the QT interval and therefore effective risk are well described; testosterone is typically protective so the QT interval in males shortens post-puberty by 20 milliseconds, whereas in females the balance between estrogen and progesterone is important and thought to underlie the increased rate of events at specific times as detailed above.
Genetics of LQTS
Long QT syndrome is caused by a disease-causing change (mutation) in the coding sequence in one of several different genes known to be associated with the disorder. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation in a gene occurs, the encoded protein product may be faulty, inefficient, absent, or overactive. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
Long QT syndrome has been shown to be caused by mutations in one of at least 15 different ion-channel genes: the KCNQ1 gene causing LQTS1; KCNH2 causing LQT2; SCN5A causing LQT3; ANK2 causing LQTS4; KCNE1 causing LQTS5; KCNE2 causing LQT6; KCNJ2 causing LQTS7; CACNA1c causing LQTS8; CAV3 causing LQTS9; SCN4B causing LQTS10; AKAB9 causing LQTS11; SNTA1 causing LQTS12; KCNJ5 causing LQTS13; CALM1 causing LQTS14; and CALM2 causing LQTS15. Mutations in KCNQ1, KCNH2, and SCN5A correlate to Long QT types 1-3 and account for the majority (60-75%) of genetically identifiable cases.
Humans inherit two copies of every gene, one 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 presentation of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (de novo) in the affected individual. The chance of passing the abnormal gene from an affected parent to offspring is 50% for each pregnancy regardless of the sex of the child.
Rarely, the mutations that cause Long QT syndrome may occur sporadically (de novo), which means that in those specific cases the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. Typically, the mutation is inherited from or “carried” by a parent. Long QT syndrome also shows variable expressivity and incomplete penetrance. In autosomal dominant disorders this means that manifestations of the disorder may not be present in all those who inherit the same altered gene for the disease. In those who develop symptoms, the specific characteristics that develop may vary greatly in range and severity from one person to another.
Several different factors may account for this variability including multiple environmental and genetic factors (e.g. modifier genes). Other factors that have been speculated to impact disease severity and expression include hormonal aspects, behavioral components, and normal variation with the nerves that serve the heart (the heart’s innervation), the autonomic nervous system. This system controls the involuntary actions of the body including regulating the heartbeat.
Approximately 20%-40% of families with a diagnosis of Long QT syndrome do not have a mutation in one of the above 15 genes, suggesting that additional as-yet-unidentified genes can also cause the disorder. More research is necessary to identify the specific genes involved in these cases.
In those with an identifiable genetic variant, the first two types of Long QT syndrome, LQTS1 (KCNQ1) and LQTS2 (KCNH2), account for approximately 75%-80% of cases, whereas LQTS3 (SCN5A) accounts for approximately 10% of cases. The remaining known genes account for less than 5% of cases and some of these variants have only been described in a few individuals.
Molecular biology of LQTS
The genes associated with Long QT syndrome produce (encode) proteins, which are major components of the cardiac ion channels of the heart, specifically potassium, sodium and calcium, but also scaffolding proteins that ensure normal channel function (e.g. ankyrin-B). Ion channels, which are pores in cell membranes, regulate the movement of electrically-charged particles called ions (e.g. potassium and sodium) through the membrane and these are ultimately responsible for cardiac activation (depolarization) and relaxation (repolarization). Mutations in these genes result in abnormal functioning of the ion channels and, in turn, affect the proper function of the heart’s electrical system leading to either continued depolarization or delayed repolarization, the net effect of which is to prolong the cardiac cell action potential and QT interval on the ECG.
Long QT syndrome affects males and females in equal numbers and has been identified in all ethnic groups. The exact incidence and prevalence of the disorder is not known. It is estimated to occur in approximately 1 in 2,000 live births from a clinical and genetic study of 44,500 newborns (neonates).
The diagnosis of long QT syndrome is a clinical one, based upon a thorough evaluation, a detailed patient and family history and a specialized test called an electrocardiogram (ECG or EKG). Individuals with unexplained history of fainting, syncope, atypical epilepsy or sudden cardiac arrest should be evaluated for Long QT syndrome. An ECG records electrical activity of the heart and may reveal abnormal electrical patterns. The ECG may be abnormal at rest, both in terms of QT interval prolongation and T-wave morphology (shape). As the penetrance of LQTS is low, many patients may have a relatively normal ECG at rest but the QT interval and morphological changes can be brought out either by standing or during the recovery period from exercise.
Molecular genetic testing can support a diagnosis of Long QT syndrome in many cases, although genetic testing is a probabilistic not deterministic outcome (it can indicate a predisposition of long QT syndrome, not whether a person will develop the condition and associated symptoms) and any identified genetic variant needs to be carefully interpreted in the context of a wider familial evaluation and correlated with clinical findings.
Treatment is aimed at preventing symptoms such as syncope or cardiac arrest. Specific medications, avoidance of triggering events and QT prolonging medication, and certain medical devices may all be used to treat individuals with Long QT syndrome. Genetic counseling is of great benefit for affected individuals and their families to understand implications for family members, recurrence risk, family planning options, and psychological adjustment to disease and/or carrier status.
The treatment of choice for most affected individuals is drug therapy with beta-adrenergic blocking agents (beta blockers). Beta blockers prevent adrenergic stimulation of the heart via the beta-receptors and can be highly effective in treating long QT syndrome. Nadolol and propranolol are longer acting beta-blockers and the agents of choice in managing the condition. Even though many patients now diagnosed are asymptomatic due to better awareness of the condition and more effective family cascade testing (i.e. identifying family members who are at risk of also having long QT syndrome), beta-blockers are still recommended if any evidence of the condition can be elicited either at rest or with provocation such as exercise stress tests. Beta blockers need to be taken daily and the failure to do so (noncompliance) by affected individuals can lead to the development of symptoms including sudden death.
Individuals for whom beta blockers are unsuccessful or contraindicated may be treated by a surgical procedure in which the autonomic nerves supplying the heart are interrupted (left cardiac sympathetic denervation or sympathectomy). The autonomic nerves release catecholamines which stimulate the heart via the beta-receptors, so this can be considered another form of anti-adrenergic therapy. The heart rhythm is controlled by the sympathetic nervous system, which controls many of the involuntary actions of the body. These nerves work to regulate the heart rhythm and this procedure can significantly reduce the frequency of arrhythmic events. During the procedure, a small cut (incision) is made in the chest wall and specific autonomic nerves supplying the heart are cut. Left cardiac sympathetic denervation is usually reserved for individuals who are considered high risk, develop symptoms despite beta blocker therapy, or are contraindicated to or cannot tolerate beta blocker therapy.
For affected individuals who have been resuscitated from cardiac arrest (whether on or off beta blockers), treatment with an implantable automatic cardioverter-defibrillator or ICD should be considered. These small devices are implanted under the skin of the chest, and wires are passed down into the heart to monitor the heart rhythm on a beat by beat basis. The device detects episodes of torsades de pointes automatically and delivers an electrical shock to restore normal cardiac rhythm. ICDs are also considered for individuals who experience recurrent syncopal events despite therapy with beta blockers. ICDs do not prevent the occurrence of torsade de pointes and, therefore, are used in conjunction with beta blockers and/or cardiac sympathectomy. An ICD is a therapy that carries significant medical and psychological complications, especially in younger individuals, and should be undertaken only after detailed consultation with appropriate medical personnel experienced in the management of LQTS and a careful consideration of the risks and benefits. Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as specific subtype; effectiveness of medications; an individual’s previous history, age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the healthcare team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
Some individuals with long QT syndrome are encouraged to avoid potential triggering events such as jumping into cold water or amusement park rides. Individuals with Long QT syndrome who wish to participate in competitive sports should be referred to a clinical expert for evaluation of risk. Affected individuals need to avoid drugs that prolong the QT interval, a full list of such drugs can be found at www.crediblemeds.org.
Drugs that block cardiac sodium channels (e.g., mexilitine, eleclazine) are being evaluated in individuals with the LQTS3, which is characterized by gain of function in ion channels and excessive sodium influx. In a series of patients with long QT 3 reported in 2016, mexilitine was recently found to significantly shorten the QT interval and reduce cardiac events in patients with LQT3. Eleclazine is currently under evaluation to assess its effects on shortening the QT intervals, safety and tolerability in adult patients with long QT 3. This study has completed recruitment for the 24-week single-blind treatment phase and the results are awaited.
Information on current clinical trials can be found at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
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