NORD gratefully acknowledges Alessandro Trancuccio, MD and Silvia G. Priori, MD, PhD, Molecular Cardiology, IRCCS, Istituti Clinici Scientifici Maugeri, Department of Molecular Medicine, University of Pavia, Pavia, Italy, and the Timothy Syndrome Alliance for assistance in the preparation of this report.
Timothy syndrome (TS), also referred to as long QT syndrome type 8 (LQT8), is a rare multisystem genetic disorder affecting the heart and several other organs, including the skeleton, metabolic system, and brain [1–3]. The most relevant heart manifestation of TS is the prolongation of the time required by the heart to complete a cycle of its electrical activity, known as the “QT interval”. TS belongs to a heterogeneous group of diseases collectively classified as “long QT syndrome” or LQTS. The QT interval prolongation predisposes patients to a high risk of developing cardiac arrhythmias and experiencing cardiac arrest from a very young age .
The main feature that distinguishes TS from other forms of LQTS is that it presents additional clinical manifestations, both heart (cardiac) and extra-cardiac. These include cardiac malformations, thickening of the cardiac walls (cardiac hypertrophy), fingers or toes that are fused together (syndactyly), facial differences, immunological defects, neurodevelopmental delay and episodes of low levels of sugar in the blood (hypoglycemia) . The Timothy Syndrome Alliance states that with more cases being identified, gastrointestinal defects have become a major concern.
These multisystem abnormalities are the result of a genetic modification that affects multiple organs and tissues of the body. TS is caused by changes (mutations) in the CACNA1C gene  that provides the instructions for the assembly of special proteins known as “calcium channels.” These channels are located on the external membrane of cells and allow calcium ions to flow into the cardiac cells. Since the calcium channels are present not only in the heart but in many other organs, multiple body systems are affected.
Available treatments include orally administrated medications (“antiarrhythmics”) and implantable devices like pacemakers (PM) or implantable cardioverter defibrillators (ICD) .
Due to the multisystem nature of this disease, its clinical presentation is remarkably complex.
TS’s key cardiac feature is the documentation of a markedly prolonged QT interval on the electrocardiogram (EKG). The QT interval is the electrocardiographic parameter representing the time required for the heart to complete a cycle of contraction and relaxation. The prolongation of this interval predisposes the heart to develop sudden alterations in the cardiac rhythm (known as arrhythmias). These cardiac arrhythmias can be very rapid and can impair the heart’s ability to pump blood to the brain, ultimately resulting in a sudden loss of consciousness (syncope), cardiac arrest, and potentially sudden cardiac death. Anesthesia and hypoglycemia are well-recognized triggers for arrhythmias in patients with TS [6–8]. Furthermore, when the QT interval is exceptionally prolonged, as is the case in patients with TS, a slowing in the conduction of the electrical impulses from the atria to the ventricles can occur. This phenomenon is called “atrioventricular block” and can result in a severe reduction of the heart rate (bradycardia).
One of the most common and peculiar extra-cardiac signs of TS is the presence of syndactyly [2,9], a condition in which two or more digits are fused together. It can be bilateral and may involve both the hands and the feet. According to a recent research study , up to 20% of individuals with TS may not present with syndactyly. Therefore, genetic testing is crucial to establish the diagnosis of TS in these patients.
Some visible signs associated with TS are specific facial differences in about 50% of patients [3,6], including low-set ears, a lower nasal bridge, a small upper jaw, baldness at birth and small and widely spaced teeth with a predisposition to cavities.
Additional extra-cardiac symptoms are a predisposition to infections (30-40% of patients [3,6]) secondary to an immunological defect and occasional episodes of low blood sugar (hypoglycemia), that may lead to fainting and, if untreated, death. Children with TS may also present with neurodevelopmental delay in up to 60% of patients [3,6]. The neurological features include autism spectrum disorders, seizures and intellectual disability.
In 2004 Splawski and colleagues  discovered that TS is caused by mutations in the CACNA1C gene, which is responsible for regulating the formation of a protein that moves calcium inside the cardiac cells (i.e. the “calcium channel”). The calcium channel is composed of a long sequence of smaller molecules, called “amino acids”. In the first cohort described by Splawski in 2004 , all patients had an identical mutation (G406R), which caused the substitution of the amino acid “glycine” (G) in position 406 with the amino acid “arginine” (R). When this gene is mutated, the closing of the channel is delayed causing too much calcium to enter the cells, which in turn determines the prolongation of the QT interval on the EKG.
TS is a dominant genetic disorder. This means that only a single copy of an abnormal gene is sufficient to cause the disease to be inherited. The abnormal gene can be inherited from either parent or it can be the result of a new mutation in the affected individual. The latter occurrence is called a “de novo” mutation and represents the most common cause of TS. However, in about 10% of patients [3,6], one parent can be a carrier of the mutation, but not in all cells of his/her body, a situation called “parental mosaicism”. This results in the possible transmission of the disease to children even though neither parent has the clinical manifestations of the disease.
From the original description in 2004, it was found that other mutations in the CACNA1C gene can cause TS. According to a recent research study, the G406R mutation is present in about 60% of patients with TS. Other mutations described in the medical literature as associated with a TS phenotype include the following: G402R , G402S , S405R , C1021R , I1166T , K1211E , A1473G  and G1911R .
In recent years, the features associated with cardiac calcium channel mutations have greatly expanded. Some CACNA1C mutations can cause LQTS without other cardiac or extra-cardiac manifestations (deemed “CACNA1C-related LQTS”). Some examples include: A28T, P381S, M456I, A582D, L762F, P857R, R858H, R860G, I1166V, I1475M, E1496K, and G1783C. These do not properly correspond to the definition of Timothy syndrome. However, other mutations (e.g. R518C, R518H)  have been associated with cardiac malformations and hypertrophy and they are classified under the name “cardiac-only Timothy syndrome” (COTS).
TS has been diagnosed in less than 100 children around the world. Because of the multisystem nature of this syndrome, very few children live to adulthood. Thanks to improved recognition of this syndrome and improved medical care, there are a number of TS individuals now in their twenties and early 30s.
The occurrence of cardiac arrhythmias or the documentation of a prolonged QT interval on the EKG usually permits the establishment of diagnosis in the first days of life. In up to 25% of patients , TS may also be suspected before birth due to abnormal heart rate in the womb (“fetal bradycardia”) but occasionally the diagnosis is made later, during early infancy. Other distinctive features such as cardiac malformations or hypertrophy, syndactyly and typical facial abnormalities are suggestive of TS. Additional symptoms such as recurrent infections, episodes of paroxysmal hypoglycemia, autism spectrum disorders, seizures and intellectual disability may also contribute to the diagnosis. Once clinical suspicion has been raised, diagnosis can be confirmed through genetic testing for mutations in the CACNA1C gene. Once diagnosis is established, evaluations including cardiology, neurology, skeletal and metabolic consultations should be done to evaluate the extent of the disease and to undertake the appropriate therapeutic measures.
Cardiac symptoms of TS can be managed through a variety of treatments, including drug therapies. An integrated approach based on different therapeutic options has made it possible to slightly improve the prognosis of patients with TS compared to the first reports in 2004 and 2005. However, the disease still has an extremely high mortality rate and few affected individuals reach adulthood.
One common treatment is orally administrated drugs called “beta blockers” (BBs), which block the effect of epinephrine thus preventing sudden increases in heart rate. BBs are currently used with success to treat other forms of genetic LQTS. However, recent data from international registries [6,7] reported that 70% of patients were treated with BBs at the time of the cardiac arrest, suggesting that the effect of BBs in preventing sudden cardiac death is not satisfactory in this particular form of LQTS.
The most effective treatment is the use of an implantable cardioverter defibrillator (ICD). This device is able to recognize when the heart experiences a life-threatening arrhythmia and delivers an electric shock that restores a normal heart rate. Considering the high mortality rate of the disease, the prophylactic implant of an ICD is often recommended in patients with TS . Pacemakers (PM) are also frequently used in infants to prevent the excessive slowing of the heart rate (bradycardia) secondary to the aforementioned atrioventricular blocks .
Other treatments address the management of the non-cardiac manifestations of the disease. Respiratory infections are common in TS and should be treated with antibiotics that do not cause QT prolongation. Surgical correction of syndactyly is possible, but it should involve careful monitoring of the heart for any complications, since the use of anesthetic drugs is a common trigger for cardiac arrhythmias in patients with TS .
Monitoring of individuals with TS 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.
A medical team may be necessary to address the other non-cardiac issues that affect the quality of life of these children. Intestinal issues are of major concern along with bouts of hypoglycaemia. The neurodevelopmental delays observed in many TS individuals may require special educational needs and therapeutic interventions.
Other pharmacological approaches aimed to shorten the QT interval and to reduce the risk of arrhythmias and cardiac arrest are currently being studied.
Since the disease is caused by an increase in calcium channel function, calcium channel blockers (i.e. verapamil) appear to be a seemingly intuitive solution. However, to date, this class of drugs has not been found to be effective in reducing the risk of life-threatening arrhythmias [25–27].
Another strategy is based on the inhibition of the sodium channel by class Ib antiarrhythmic drugs (i.e. mexiletine). This approach has been shown to be effective in long QT syndrome type 3 and one study reported its efficacy in reducing the duration of the QT interval in a patient with TS . Also ranolazine, an antianginal drug with a multiple effect on different cardiac ion channels, has been hypothesized to be effective thanks to its action on the sodium current [29,30].
Finally, promising results, although only experimental, have been obtained for roscovitine (Seliciclib). Roscovitine is an anti-cancer drug developed in the late 90’s  which inhibits some cellular molecules called “cyclin-dependent kinases” (CDKs), that are important in regulating the cell cycle. Experimental studies[32–34] conducted in cells derived from patients with TS have shown that roscovitine is able to correct some cellular abnormalities that are at the basis of the genesis of arrhythmias in TS, but further studies are needed to confirm these preliminary observations.
Since the non-cardiac and non-neural issues involve non-excitable cells, research is needed to understand the calcium signalling that may be abnormal; this abnormal signalling is likely the cause of these multisystem concerns.
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