About Long QT Syndrome

What is the Long QT Syndrome?
The Long QT Syndrome (often abbreviated as LQTS) is a disorder of the electrical system of the heart. It particularly involves the process called repolarization, or the recharging of the electrical system after each heart beat. The QT interval is a quantity measured on the electrocardiogram (ECG or EKG). The duration of the QT interval is a measure of the time required for depolarization and repolarization to occur. In the long QT syndrome, the duration of repolarization is longer than normal, thus, the QT interval is prolonged. Prolongation of the QT interval renders patients vulnerable to a very fast, abnormal heart rhythm (an "arrhythmia") known as torsade de pointes. When this rhythm occurs, no blood is pumped out from the heart, and the brain quickly becomes deprived of blood, causing the usual symptoms of sudden loss of consciousness (syncope) and sudden death.

What causes the Long QT Syndrome?
It is caused by dysfunction of protein structures in the heart cells called ion channels. These channels control the flow of ions like potassium, sodium and calcium molecules. The flow of these ions in and out of the cells produces the electrical activity of the heart. Abnormalities of these channels can be acquired or inherited. The acquired form is usually caused by prescription medications, and a list of known agents can be viewed by returning to the home page and selecting the "drugs to avoid" item. Sometimes strokes or other neurologic disorders can cause acquired LQTS.

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The inherited form occurs when a mutation develops in one of several genes which produce or "encode" one of the ion channels which control electrical repolarization. The mutant gene produces abnormal channels to be formed, and as these abnormal channels are not as efficient as the normal channels, the electrical recovery of the heart takes longer. This is manifest on the electrocardiogram (ECG, EKG) by a prolonged QT interval. QT prolongation makes the heart vulnerable to a fast, abnormal heart rhythm known as "torsade de pointes".

The SADS Foundation is concerned with both the inherited and acquired forms. Inherited LQTS is still often undiagnosed and untreated,so the affected persons remain at risk for syncope and sudden death. Since inherited LQTS is a very treatable disorder, and the syncope and sudden death can be prevented, SADS believes it is imperative that physicians, other health care providers and the public be informed about this condition, and the diagnostic and treatment options. SADS is quite concerned also about medication induced LQTS. There are over 50 commonly used prescription medications which have been associated with QT prolongation and/or torsade de pointes. SADS is actively involved in educating physicians and the public about this issue.

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What are the symptoms?
Sudden loss of consciousness (the medical term is 'syncope') and sudden death are the common symptoms. They are due to the arrhythmia torsade de pointes, and usually occur during physical exertion or emotional excitement like anger, fear or startle, but may occur during sleep, or arousal from sleep. Common startle events include sirens, the telephone and the alarm clock. It is less common for the syncope or sudden death to occur when the person is awake and at rest. The particular trigger for the symptoms depends to some degree on the specific gene abnormality (see the section on genetics). Exercise induced syncope usually occurs right during the exercise, but occasionally occurs within a few seconds or a minute or two after the exertion. In patients who experience syncope the torsade de pointes rhythm reverts spontaneously to normal, usually within about 1 minute or less. When this occurs, the patient quickly regains consciousness, usually without disorientation or residual symptoms, although fatigue may be present. When the torsade rhythm persists for a longer time, however, it degenerates into ventricular fibrillation and the outcome is death unless electrical defibrillation is provided.

Not all patients who have this condition have symptoms; at least one-third, and probably more, never develop any symptoms. In the others, some have just one or two syncopal spells as children, and none thereafter, whereas, some have many episodes over a number of years. The symptoms may begin as early as the first days or weeks of life, or as late as middle age. Most commonly, however, the symptoms first occur during pre-teen and teenage years. The symptoms start earlier in males than females, beginning on average at approximately 8 years in males and 14 years in females. Because many affected persons never have symptoms, the absence of a history of syncope or sudden death in a family does not at all guarantee the absence of LQTS in the family.

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Who is at risk for having Long QT Syndrome?
Children and young adults with unexplained syncope or cardiac arrest, members of families with an unexplained sudden death in a young person, and blood relatives of patients with known LQTS. There are a number of causes of syncope in young persons, and several causes of cardiac arrest. Please see the sections on symptoms and diagnosis for the characteristic features of LQTS and the differences from these other causes.

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How common is LQTS?
LQTS is an important cause of sudden, unexpected death and syncopal spells in children and younger adults. The exact number of affected persons is unknown, but we estimate that LQTS is present in 1:5,000 persons in the USA (over 50,000 people) and may cause as many as 1,000 deaths (mostly in children and young adults) each year. It is present in all races and ethnic groups, but it is not certain if the frequency is the same in all races.

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What are the Genetics of Long QT Syndrome, and how is it inherited?
LQTS is caused by mutations of at least 6 genes, and possibly more. Five different genes have so far been found. The location of a sixth gene is known, but the actual gene has not been found. In some families with clear cut LQTS, no mutations of these 5 known genes were found during the initial testing, so other genes were assumed to exist. Since then, however, some of these families have been retested, using better technology, and a mutation of a known gene has been identified. Thus, at present it is not known if more genes exist or not. Certainly, now that the human genome has been nearly fully described it will be possible to find out.

The five genes known at the present time include four which form potassium channels and one which forms the cardiac sodium channel. (1) The KCNQ1 (KVLQT1 ) gene on chromosome 11 encodes for a potassium channel. Mutations of this gene cause the LQT1 form of LQTS. LQT1 is the most common form of LQTS. (2) The HERG gene on chromosome 7 encodes for a potassium channel also, and nutations cause the LQT2 form. It is the second most common form of LQTS. (3) The SCN5A gene is on chromosome 3 and it encodes for the cardiac sodium channel. Mutations of this gene cause LQT3. LQT3 is uncommon and accounts for only a few percent of genotyped LQTS patients. (4) LQT4 is on chromosome 4, but the actual gene has not been found. (5)The LQT5 gene is known as MinK, or KCNE1, on chromosome 21. It coassembles with the KCNQ1 gene (KVLQT1) to produce the potassium channel. Mutations of this gene, like those of KCNQ1, produce the LQT1 form of LQTS. (6) The MiRP1 gene is known as LQT6, and it also resides on chromosome 21. It coassembles with the HERG gene to produce the potassium channel. Mutations of this gene, like those of HERG, cause the LQT2 form of LQTS.

As noted previously, these genes produce proteins which make cardiac cell structures known as ion channels. About 200 different mutations of these genes has been found so far. There is some variation of the electrocardiographic findings and patient symptoms depending upon which gene and which mutations are involved. Our current estimate of the frequency of these genes is as follows. The LQT1 form, from KCNQ1 (KVLQT1) or KCNE1 (MinK) gene mutations, is the most frequent, accounting for approximately 55-60% of genotyped patients. LQT2, from HERG or KCNE2 (MiRP1) mutations, is next at about 35-40%, and LQT3, from SCN5A mutations accounts for about 3-5%. Patients with two mutations seem to account for less than 1% of all patients, but this may change as more patients are studied with the newer genetic techniques.

Historically, two different clinical forms of LQTS have been described, the Jervell, Lange-Nielsen (J, L-N) and the Romano-Ward (R-W) forms. J, L-N is rare, but generally produces earlier and more severe symptoms than the R-W form.

J, L-N was described in 1957. It is associated with profound deafness at birth as well as LQTS. and is inherited by autosomal dominant transmission. It occurs when both parents have an abnormal LQTS gene, either KCNQ1 (KVLQT1) or KCNE1 (MinK) and a child gets both abnormal genes, one from each parent. Statistically, each child of this couple has a 25% chance of getting both abnormal genes (the "homozygous" state), a 50% chance of getting just one abnormal copy (the "heterozygous" state) and a 25% chance of getting both normal genes and not having LQTS. When a child does get both abnormal genes, they are "homozygous" if both parents have the same abnormal gene, or "compound homozygous" if one parent has an abnormal KCNQ1 and the other an abnormal KCNE1 gene. J, L-N is rare because it is not likely that both parents will have LQTS. J, L-N usually occurs when cousins marry (called a consanquineous marriage).

The inheritance of J, L-N is complex, and demonstrates a new genetic paradigm. The J, L-N syndrome (which includes congenital deafness) is inherited as an autosomal recessive condition, because at least one normal KCNQ1 gene is necessary to develop a functioning ear potassium channel and for the hearing mechanism to develop. In these homozygous patients, they have only mutant KCNQ1 genes, thus, deafness. However, the heterozygotes, such as the parents and some siblings, with normal hearing, actually have autosomal dominant LQTS, just like the Romano-Ward LQTS patients. The mutations which have been found in J, L-N families have usually produced a more "mild" form of long QT syndrome in the heterozygotes, with a shorter QT interval and less symptoms than the usual LQTS patient, and these family members were misdiagnosed as normal for many years. We now know the heterozygous in the J, L-N families do have Romano-Ward autosomal dominant LQTS and may be at risk for LQTS events. Thus, the parents and siblings of the J, L-N child need to be carefully screened for LQTS.

The second and common form of the syndrome was described in 1963 by Drs. Romano in Italy and Ward in Ireland. In this form the hearing is normal. The patient inherits one abnormal copy of an LQTS gene, and has one normal copy of that gene. It is, therefore, transmitted by autosomal dominant inheritance. Each child born to an affected parent has a 50% chance of receiving the abnormal copy and a 50% chance of receiving the normal copy.

In both forms of LQTS the frequency of inheritance is equal in males and females. In general, females have symptoms over a longer period of time than do males.

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How is the syndrome diagnosed?
It is usually suggested by the occurrence of syncope, cardiac arrest or sudden death. The diagnosis is made from a prolonged QT interval on the ECG. A clearly long QT interval is present in 60% to 70% of affected persons, but the QT is normal to only borderline prolonged in 30-40%. Sometimes the QT prolongation is overlooked by medical professionals even when present, so when a patient is concerned about LQTS it is appropriate to ask the Doctor to specifically evaluate the QT interval. Overall, about 12% of LQTS patients have a normal QT interval on their baseline, resting ECG. Thus, a normal QT interval does not necessarily exclude long QT syndrome. In those patients with a normal to borderline interval, the diagnosis may be difficult and other testing is necessary. Other testing may include evaluation of additional ECG's on the patient, as the QT interval varies from ECG to ECG and may be prolonged on other records. Also quite helpful is the examination of ECG's on parents and siblings; since this is a genetic disorder, one parent and typically other siblings will be affected and their QT may be diagnostically prolonged. Additional tests which may be helpful for diagnosis include exercise ECG's and ambulatory ECG monitoring (Holter monitors, event monitors). Electrical heart catheterization (EPS testing) is generally not helpful in identifying LQTS patients.

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What is the treatment, and who should be treated?
All symptomatic patients should receive treatment. The usual treatment is beta-blocker drug therapy. The goal of therapy is the resolution of symptoms and in many cases the resolution of certain ECG abnormalities. Current research suggests that treatment might best be tailored to the specific gene type. Beta-blockers are quite effective in the LQT1 patients, and are the treatment of choice. Patients with LQT3, due to sodium channel abnormalities, might be best treated with medications which affect the sodium channel, such as the drug mexilitine. It has not yet been demonstrated that such drugs are effective in preventing syncope and death but research studies to prove or disprove this are underway. Also, pacemakers or the implantable defibrillator may be important therapy for LQT3 patients. In patients with LQT2, potassium administration has been shown to shorten QT duration. This also is a research treatment, and it is not known if this treatment is effective, and particularly over a period of time. Beta-blockers are effective in many LQT2 patients. For any patient who has experienced a cardiac arrest, particularly if already on drug treatment, or who continues to have syncope in spite of medications, might best be treated with the implantable defibrillator.

Asymptomatic children and young adults should be treated as well. Some will become symptomatic and sudden death may be the first symptom. Thus, preventative treatment is required, usually with beta-blockers. At least one-third, probably more, of gene carriers never develop symptoms. Unfortunately, we cannot predict with any accuracy which LQTS patient will subsequently have symptoms and which will not. The beta-blocker treatment is very safe and usually well tolerated. Therefore, children, adolescents and young adults at the time of diagnosis should be treated even in the absence of symptoms, since they have an unknown but significant chance of subsequently developing symptoms including sudden death.

When a person is older at the time of diagnosis, for example 40-45 years or older, and has been asymptomatic life long or for many, many years, it may not be necessary to treat them, as their risk of developing symptoms at these later ages is quite low, though not zero. They do need to avoid low blood potassium (caused by diuretic drug use, vomiting or diarrhea) and the many drugs which lengthen the QT interval and which can cause LQTS themselves. You can download a list of these drugs and search for a drug or print the list-- be sure to print out this list if there is any concern you have LQTS, and show the list to the Doctor every time you are prescribed a medication, in order to make sure it is not on the list.

Once treated, it is very important that the medication be taken every day and not missed or omitted. The medications are not curative; they only provide protection while being taken and the protecting effect is gone within a day or two of stopping the medication. After that the risk of syncope or sudden death is the same as if the patient had not taken the medication at all. Parents should teach their children about the importance of daily medication, and should make sure each daily dose is taken. Physicians need to discuss this directly with all patients, but particularly children.

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What about exercise?
We think it advisable that long QT patients not participate in competetive sports, since so many times symptoms are precipitated by physical exertion and/or emotions. Once properly treated, however, many LQTS patients can participate in recreational sports. We advise moderation and the "buddy" system. Friends or relatives who are often with the patient are the "buddies". They should be informed about the condition and the potential for syncope. They should be instructed to call for help, including 911, if syncope occurs in their friend. Then, arrange to have one or more "buddies" present during the exercise. It is often advisable for family members to learn CPR in order to provide immediate resuscitation efforts if a family member has an event.

If you would like more information...
Please view the SADS webpage www.sads.org, or call the SADS Foundation toll free at 1-800-STOP-SAD(1-800-786-7723) to request an information packet or get a referral to a knowledgable physician in your area. Please register with the Foundation by using our on-line registration which is accessed from the home page. This will provide you with periodic mailings of updates and important information, including our periodic newsletter and medical alert updates.

We would love your help! If you would like to participate in the great work that the SADS Foundation is doing, including education, support of research, patient care services and family support programs, please send whatever generous contribution to the SADS Foundation, 508 East South Temple, Ste 20, PO Box 58767, Salt Lake City, UT 84102, to assist in our life- saving efforts. Donations are fully tax deductible and you will receive a receipt for your records. Thank you.

— G. Michael Vincent, M.D.

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