NORD gratefully acknowledges Emily Norton, NORD Editorial Intern from the University of Connecticut, and Silvia G Priori, MD, PhD, Professor of Cardiology, University of Pavia, Director of Cardiology at ICS Maugeri Hospital, Pavia Italy, for assistance in the preparation of this report.
Timothy syndrome is a rare genetic disorder that affects the heart and several other organs. The most obvious manifestation is the abnormally long repolarization (QT interval) in the heart that predisposes patients to cardiac arrhythmias and sudden cardiac death. Unlike other forms of long QT syndrome, patients with Timothy syndrome also present with cardiac malformations, thickening of the cardiac walls (cardiac hypertrophy) and enlargement of the heart (cardiac dilatation).
Timothy syndrome is also associated with abnormalities of fingers or toes that are fused together through webbed skin between the digits (cutaneous syndactyly), specific facial features, a weakened immune system, developmental delays and episodes of low levels of sugar in the blood (hypoglycemia).
Timothy syndrome is caused by DNA changes (mutations) in the CACNA1C gene that provides instructions for making calcium channels in the heart. These channels allow calcium to enter cardiac cells. Since these calcium channels are not only present in the heart but also in many other organs, symptoms of Timothy syndrome are widespread. Use of beta blockers, pacemakers, and implant of cardiac defibrillators can be used to reduce arrhythmias and prevent cardiac arrest. The other symptoms should be managed through close surveillance and avoiding triggering factors.
One defining feature of Timothy syndrome is a long QT interval on an electrocardiogram (EKG). The QT interval is the time required for the heart to complete ventricular contraction and relaxation. The delayed return to resting state predisposes the heart to develop ventricular arrhythmias and functional heart blocks. These heart arrhythmias can be very rapid and impair the ability of the heart to pump blood to the brain: for these reasons patients may experience fainting episodes that are the manifestation of arrhythmias and should prompt hospitalization. Anesthesia may also trigger arrhythmias, and for this reason surgeons and the anesthesiologists should be aware that the patient has Timothy syndrome and discuss with the electrophysiologist the management of the patient and his/her monitoring during surgery.
It is important to know that not all individuals with Timothy syndrome present with cutaneous syndactyly. The diagnosis of Timothy syndrome in these patients can be established only with genetic testing. In the patients that present with syndactyly, it involves the index, middle, ring, and little fingers, as well as toes two and three. The syndactyly may be on one side of the body or both, and can be between two, three, or four fingers.
Timothy syndrome is also associated with specific facial characteristics. These include low-set ears, a lower nasal bridge, a small upper jaw, baldness at birth and for the first two years of life, followed by thin hair, and small, widely spaced teeth with a predisposition to cavities. Other findings include frequent infections, rigid joints and occasional episodes of low blood sugar (hypoglycemia) that may lead to fainting and if untreated may cause death.
Children with Timothy syndrome may also have developmental delays, including autism spectrum disorders that can involve difficulty communicating, socializing, or making correct movements. Seizures, strokes, and blindness can also occur as a result of developmental delays in those with Timothy syndrome.
Timothy syndrome is caused by mutations in the CACNA1C gene. The CACNA1C gene is responsible for regulating the formation of a protein that moves calcium inside cardiac cells in a specific phase of the cardiac cycle. When this gene is mutated, the closing of the channel is delayed, causing too much calcium to enter cells: this excess of calcium prolongs the QT interval in Timothy syndrome patients.
Most patients withTimothy syndrome have a specific CACNA1C gene mutation. A few patients have been reported in the medical literature with different CACNA1C gene mutations that are associated with long QT interval and may or may not be associated with syndactyly.
In most affected individuals, the disorder is due to a spontaneous (de novo) CACNA1C gene mutation that occurred only in the egg or sperm cells of the parents or that developed in the fertilized egg during the initial phase of development of the embryo. In such situations, the disorder is not inherited from the parents. Timothy syndrome may also be transmitted by an affected parent to a child in an autosomal dominant manner.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Timothy syndrome has been diagnosed in an extremely low number of individuals in the world because it has a high mortality, it is a complex disease, and few affected individuals reproduce.
Diagnosis of Timothy syndrome is usually made in the first few days of life due to symptoms such as arrhythmias or because the prolonged QT interval is observed. Occasionally the diagnosis is established at more advanced age during early infancy.Timothy syndrome may also be suspected before birth due to abnormal heart rate in the womb. A combination of a prolonged QT interval, additional heart problems, webbed fingers and toes, and characteristic facial features are suggestive of Timothy syndrome. Additional symptoms such as autism, communication problems, seizures, or movement disorders also contribute to the diagnosis. Timothy syndrome can be confirmed through genetic testing for disease-causing variants or mutations in the CACNA1 gene. After diagnosis, evaluations such as electrocardiograms, neurological assessment, and skeletal consultation should be done in order to evaluate the extent of the disease and symptoms.
Cardiac symptoms of Timothy syndrome can be managed using a variety of treatments. Beta blockers, which block the effect of epinephrine, are currently used to treat longer QT intervals and to prevent sudden increase in heart rate. However, there is currently limited information to show whether these drugs are effective to prevent sudden cardiac death. Pacemakers are frequently used to prevent AV block that is a slowing of the speed of propagation of cardiac impulse from the atria to the ventricles and may result in slowed heart rate. Pacemakers have been successful to prevent AV block also, when implanted in the first few days of life. One of the most important treatments to prevent sudden cardiac death is the implantable cardioverter defibrillator (ICD). This device is able to recognize when the heart experiences a life threatening arrhythmia and it will deliver an electric shock to the heart in order to restore a normal heart rate. Considering the high lethality of the disease, the prophylactic implant of an ICD is often recommended to patients with Timothy syndrome.
Other treatments include managing secondary effects of the condition. Respiratory infections are common with Timothy syndrome, and should be treated with antibiotics that do not cause QT prolongation and with steroid drugs when necessary. Surgical correction of syndactyly is possible. Because anesthesia is a common trigger for cardiac arrhythmia, surgery should involve monitoring the heart for any complications. Surveillance of individuals with Timothy syndrome should include frequent blood sugar measurement and cardiac assessments. All drugs or dietary practices that may contribute to lengthening the QT interval or lowering blood sugar should be avoided.
Drugs targeting channels through the cell membrane are being studied as a treatment to shorten the QT interval, restore one-to-one conduction, and reduce the risk of arrhythmias. Specifically, blockers for sodium and calcium channels are being examined. Though there has been some effectiveness using sodium channel blockers for Timothy syndrome, there is no data available to support regular use.
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