What are the other Names for this Condition? (Also known as/Synonyms)

• Long QT Syndrome 8 (LQT8)
• Long QT Syndrome with Syndactyly
• LQT8 (Long QT Syndrome 8)

What is Timothy Syndrome? (Definition/Background Information)

• Timothy Syndrome is a disorder that affects the heart, digits (toes and fingers), and nervous system (brain and nerves). It is a type of long QT syndrome. Long QT syndrome refers to a prolonged QT interval measurement seen on the electrocardiogram
• Symptoms of Timothy Syndrome include fusion of the skin between fingers or toes (syndactyly), distinctive facial features, and congenital heart defects. Additional symptoms may include developmental delay, intellectual disability, and autism spectrum disorders
• There are two forms of Timothy Syndrome, classified based on signs and symptoms:
  • Type 1, known as classic type, includes all of the symptoms described above
  • Type 2, or atypical type, causes a more severe form of long QT syndrome and does not appear to include syndactyly
• Both types are caused by mutations in the CACNA1C gene and are inherited in an autosomal dominant manner
• The treatment of Timothy Syndrome is focused on managing cardiac symptoms. This might include medications such as beta-blockers, placement of defibrillators, and pacemakers

(Source: Timothy Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Timothy Syndrome? (Age and Sex Distribution)

• Timothy Syndrome is a rare congenital disorder, with less than 20 cases reported in the medical literature
• The presentation of symptoms may occur soon after birth and in infancy
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Timothy Syndrome? (Predisposing Factors)

• A positive family history may be an important risk factor, since Timothy Syndrome can be inherited
• Currently, no other risk factors have been clearly identified for the syndrome

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Timothy Syndrome? (Etiology)

• Timothy Syndrome is caused by mutation(s) in the CACNA1C gene, which codes for a component of calcium channels
• Calcium channels are necessary for the transport of calcium. Calcium plays crucial roles in cell-cell communication, proper contraction of muscles, and regulation of gene expression 
• The CACNA1C gene mutations may either arise sporadically, or be inherited from an unaffected parent with the gene mutation in germ cells (egg and sperms) only, and not other body cells (such individuals are “mosaic” for CACNA1C gene mutation)
• Timothy Syndrome is inherited in an autosomal dominant manner

Autosomal dominant mode of inheritance: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

What are the Signs and Symptoms of Timothy Syndrome?

The signs and symptoms of Timothy Syndrome may vary among affected individuals in type and severity, and may include:

• Very frequently present symptoms in 80-99% of the cases: Cardiomegaly
• Frequently present symptoms in 30-79% of the cases: Bronchitis

Occasionally present symptoms in 5-29% of the cases:

• Generalized hypotonia
• Hypocalcemia
• Hypothyroidism
• Patent ductus arteriosus
• Patent foramen ovale
• Pneumonia
• Seizures
• Tetralogy of Fallot
• Ventricular septal defect

In addition to the above, the following signs and symptoms may be present in some affected individuals:

• Cutaneous syndactyly
• Depressed nasal bridge
• Global developmental delay
• Microdontia
• Prolonged QT interval
• Recurrent infections
• Round face
• Thin upper lip vermilion

(Source: Timothy Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Timothy Syndrome Diagnosed?

Timothy Syndrome is diagnosed on the basis of the following information:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Laboratory tests
• Tests to check heart function (such as via electrocardiography and echocardiography)
• Imaging studies
• Biopsy studies, if necessary

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Timothy Syndrome?

The complications of Timothy Syndrome may include:

• Traits of autism spectrum disorder
• Arrhythmia 
• Cardiac arrest
• Sudden death

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Timothy Syndrome Treated?

There is no cure for Timothy Syndrome, since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops.

How can Timothy Syndrome be Prevented?

Timothy Syndrome may not be preventable, since it is a genetic disorder.

• Genetic testing of the fetus during pregnancy may help in a better understanding of having a child with Timothy Syndrome
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders
• Regular medical screening at periodic intervals with tests and physical examinations are recommended

What is the Prognosis of Timothy Syndrome? (Outcomes/Resolutions)

• The prognosis of Timothy Syndrome is dependent upon the severity of the signs and symptoms and associated complications, if any
• There is a likelihood of arrhythmia and cardiac arrest leading to sudden death in some affected children, specifically in the atypical type (type 2) of Timothy Syndrome
• Individuals with mild conditions have better prognosis than those with severe symptoms and complications
• Typically, the prognosis may be assessed on a case-by-case basis

Additional and Relevant Useful Information for Timothy Syndrome:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/