Studying patients with Timothy Syndrome

Dr Mark Walsh MB BCh BAO, MRCPCH, MRCPI, Paediatric Cardiologist & Heart Rhythm Specialist

Timothy Syndrome (TS) is an extremely rare genetic condition that causes abnormal calcium signalling in the body.

In the heart, this causes susceptibility to both abnormally fast and slow heart rhythms; its most prominent clinical feature is QT prolongation. This means that the electrical interval between the heart contracting and the heart relaxing is prolonged.

Sometimes this condition is so severe it can require pacing at a very young age. Patients are also at risk of fast heart rhythms and sometimes an internal cardiac defibrillator is required.  

My first experience with TS was a patient that I encountered while I was working at University Hospital Bristol, who was born prematurely.

She had profound QT prolongation, and required medications to support her heart rate and blood pressure. She had fused fingers, which is one of the common signs of TS. Her genetics subsequently confirmed that she did indeed have TS.

When researching medical management and the natural history of the condition, I was surprised by the lack of literature on TS. The published literature consisted mostly of case reports, so it was very difficult to ascertain what the longer-term implications were for my patient. 

Through a collaborative network of colleagues and very helpful parents, we set about collecting information on all of the TS patients that had been seen in the United Kingdom over a 24-year period.

We found 6 patients in total, which shows just how rare the syndrome actually is. Four of the 6 children were still alive at this current time. Two patients have required pacemaker implantation and 2 have required internal cardiac defibrillators.

What was most evident was the incidence of cardiac arrest during anaesthesia, and interestingly, the cardiac arrests were of multiple aetiologies. It is evident from this, that if undiagnosed, the risk of mortality is very high. 

The information that we gleaned from the study helped us to manage our patient and manage the parent’s expectations. It also helped us to give the parents some information as to what may lie ahead for their daughter.

On a positive note, one of the patients in the study was alive, living independently into her late twenties. This gave the parents hope, that while the medical therapy seemed very intensive at present, there was the potential that there could indeed be a good long-term outcome. 

With increasing research into the syndrome and its genetic basis, it is clear that there are other variants of TS that are caused by different changes in the culprit gene. This is a common phenomenon with rare conditions, first the very severe cases are described, and as knowledge of the condition improves, different variants are discovered.

Our understanding of this condition and the more subtle changes that can be seen in the TS gene is evolving all of the time. With the advent of more advanced genetic testing, it is likely that more cases of subtle developmental delay may be attributed to changes in the TS gene.

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