Overview 

Teamwork is a dynamic process which involves healthcare professionals from various disciplines and specialities sharing skill sets and knowledge in the assessment and planning of effective patient care.¹This interprofessional collaboration between the multidisciplinary team is necessary for chronic long-term illnesses, such as Timothy syndrome, to improve patient outcomes in the future and have an overall positive impact on the patient's quality of life. This is because it facilitates coordinated care and effective communication. Rare genetic conditions, like Timothy syndrome (TS), need to be managed appropriately by a multidisciplinary team consisting of a variety of professionals due to this diseases’ complexity and its effect on multiple organs in the body. This article will focus on cardiologists, geneticists and neurologists; however, there are also many other members of the multidisciplinary team, such as social workers and speech therapists. Therefore, utilising a multidisciplinary approach to care in Timothy syndrome ensures more tailored and comprehensive patient-centred care, which leads to better health outcomes. It was found that the prognosis of children with Timothy syndrome was poor, with 59% of these children facing a life expectancy of <2.5 years.²

TS is a rare genetic condition typically diagnosed within the first few days of life.³ Katherine Timothy was one of the key founders of TS and identified the conditions underlying cause It was associated with changes in the CACNA1C expression, which encodes the L-type calcium channel.⁶ As a result, when the calcium channels are formed, the amino acid glycine (Gly) is replaced by arginine, a different amino acid.⁴ This damages the formation of calcium channels, which impairs both the structure and function of the channels.⁷ This means the L-type calcium channels will stay open for longer, which leads to an abnormal increase of the number of calcium ions flowing into cells, particularly impacting the heart, brain and other tissues. Prolonged QT Syndrome, syndactyly (webbed feet and fingers), neurodevelopmental delay, and low blood sugar are common characteristics of TS; however, there has been variation between patients' clinical manifestations, possibly attributed to a patient’s genetic background.⁵ The CACNA1C gene also has different versions called isoforms, and their expression can affect structural and functional changes in the L-type calcium channels.⁵ Additionally, Timothy syndrome has three different types: TS1 will lead to multisystem involvement as previously discussed, but TS2 clinical manifestations are usually isolated cardiac issues, or symptoms similar to TS1, but without syndactyly.^{6 7} TS3 presentation includes cardiac and hand anomalies. To diagnose the specific type of TS, patients should have their CACNA1C gene fully sequenced to determine which type of TS they have.¹² Since there is no cure for TS, treatment is focused on managing symptoms, including life-threatening heart complications caused by prolonged QT syndrome, through the use of heart medications such as beta blockers. Without treatment, survival is unlikely with this disease; and so, this highlights the need for an early diagnosis, as well as a multidisciplinary approach to care involving cardiologists, neurologists and geneticists.⁷

Role of cardiologists 

As discussed above, TS is characterised by prolonged QT syndrome caused by abnormal function of L-type calcium channels. A QT interval is the amount of time needed for the heart’s ventricles to contract and relax, which is called depolarisation; however, TS causes this cycle to be prolonged. This occurs because the increase in calcium ions impacts the heart's resting phase after contraction, known as repolarisation, negatively impacting the heart's normal rhythm.⁸ This dysfunction can lead to arrhythmia, ventricular fibrillation and increased risk for sudden cardiac arrest.² It was shown that ventricular tachyarrhythmia was one of the leading causes of death in TS patients.² Cardiologists, therefore, play a central role in TS management due to the disease’s significant cardiac involvement. Also, TS can be diagnosed and assessed during infancy or in-utero during a prenatal ultrasound to assess the foetal heart rhythm and rate,¹³ but once born, cardiologists can use other assessment tools such as an electrocardiogram (ECG) to further examine patients' heart rhythm. They also use electrocardiography, a imaging test done after birth to examine abnormalities in the heart's structure and function. 

Pharmacological management is essential for patients with TS due to the reasons mentioned prior. Beta blockers such as nadolol and propranolol can be prescribed to reduce arrhythmias as they block beta-1 adrenergic receptors in the heart, decreasing the heart rate. However, beta-blocker medication may be ineffective in some cases and can aggravate the symptoms of TS.² Additionally, due to increased calcium-dependent insulin secretion of islets beta cells, beta-blocker medication is more inclined to cause hypoglycemia (low blood sugar), with a frequency of 72%.²Another medication used are sodium channel blockers such as mexiletine, which has had a positive correlation on reducing the QT interval, especially in combination with routine beta blocker medication.² Additionally, besides medications, implantable cardioverter-defibrillator (ICD) and pacemakers are also available to support the corrections of abnormal cardiac events.²

Given the potential operative risks, cardiologists play a key role in surgical planning and working within the surgical multidisciplinary team, which consists of anaesthesia doctors, ODPs (operating department practitioners), and scrub nurses to continuously monitor the patient's condition, therefore preventing the risk of further complications. In addition, cardiologists monitor for arrhythmias and blood sugar levels especially during surgical intervention. 

Role of neurologists 

Next, we will move on to the role of the neurologist in the management of TS. The increase of calcium ions from the L-type calcium channels results in an excess of fluid moving into the cells via osmosis, which results in swelling of the area around the brain, in turn, disrupting the electrical activity of the brain, therefore TS patients suffer an increased risk of seizures and potential neurological impairments,⁹ including autism, developmental delay, intellectual deficits, and seizures.⁹

In order to evaluate these issues, neurologists may need to perform a variety of diagnostic tests, such as an electroencephalogram (EEG), which monitors the electrical activity in the brain.¹⁰ They may also perform neurodevelopmental assessments; examples include the Prechtl General Movements Assessment (GMA) and Hammersmith Infant Neurological Examination (HINE); which are useful to detect early signs of motor and cognitive delays.¹¹ Therefore, if the patient is diagnosed with autism and cognitive delay, the neurologist can refer the patient to behavioral and communication therapy, which is designed to resolve challenges in social, language and behavioural difficulties. Neurologists can also prescribe anti-seizure medication such as levetiracetam and sodium valproate, which aid in managing seizure activity.¹² 

Role of geneticists 

Another key member of the multidisciplinary team is the geneticists, who play a critical role in early diagnosis and prompt management of TS. This syndrome is inherited in an autosomal dominant manner, which means only one copy of the mutated CACNA1C gene is needed to cause the disorder.¹³ However, most commonly, the mutation arises de novo (newly occurring in the affected individual rather than being inherited from a parent).¹³ Therefore, genetic testing is essential to confirm TS diagnosis early and consider treatment options. Genetic testing for Timothy syndrome analyses the CACNA1C gene for mutations through the use of targeted sequencing, multigene panels, or whole exome sequencing.¹³ it is also important to provide genetic counselling to families to provide education and inform them on the diagnosis, inheritance patterns and treatment. Geneticists go beyond diagnosis to advance research in various gene therapies. One gene therapy approach involves the use of antisense oligonucleotides (ASOs), which adjust the defects on the calcium channels, restoring its normal function.¹⁴

Summary 

TS is a rare genetic disorder, the genetic mutation leads to changes in the CACNA1C expression, which encodes the L-type calcium channel. This mutation commonly arises de novo and is inherited in an autosomal dominant manner. This mutation impacts multiple organs in the body, in particular the heart, brain and pancreas, leading to low blood sugars, arrhythmias, neurodevelopmental delay and potential cardiac arrest. Therefore, a multidisciplinary approach is required, consisting of cardiologists, neurologists and geneticists in its early diagnosis and management. 
Having a child with TS can be a very challenging and emotional period for parents navigating treatment options and understanding their child’s condition, as it is rare among infants. This uncertainty regarding the poor overall prognosis and the need for constant monitoring in particular arrhythmias, AV block, seizure activity and social challenges with syndactyly, only increases anxiety amongst parents. Therefore, it is important to have genetic testing for early diagnosis and support from healthcare professionals.