Patient Experience: Living with Timothy syndrome

pharmafile | October 26, 2020 | Feature | Business Services, Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing |  Timoty syndrome, feature, patient experience, rare disease 

Thirteen-year-old Calvin Muir lives with the ultra-rare genetic condition Timothy syndrome. Like many parents of rare disease patients, his mother Sophie had a long and uphill struggle to secure a diagnosis, but together the two have helped push research into the condition and have even made a film.

Can you give us a bit of background on your son Calvin’s condition, Timothy syndrome?

Timothy syndrome (TS) is a rare, genetic condition caused by changes to a gene called CACNA1C. In most children diagnosed with Timothy syndrome and in Calvin’s case, the change in the CACNA1C gene occurred by chance (de novo) and was not found in myself or my husband. In some cases, however, parents without symptoms have been found to carry a pathogenic CACNA1C gene variant (mosaicism) in some of their cells which means the variant can be passed on from parent to child.

The children present with a spectrum of affectedness within the CACNA1C gene. Most children with Timothy syndrome have abnormal heart function, abnormal heart structure, neuronal developmental delays, immunodeficiencies, endocrinological dysfunction, effects on smooth muscle and skeletal muscle, facial anomalies, syndactyly (joined fingers or toes), or mild dental, skin, eye and hair anomalies. Some of the children with Timothy syndrome have: significant episodes of low blood sugar levels (hypoglycemia), seizures and an unusually low body temperature (hypothermia).

There are three types of Timothy Syndrome:

TS1 is diagnosed when a genetic test identifies an amino acid change of G406R in exon 8A of CACNA1C. It is often identified at birth if an infant presents with serious cardiac concerns and syndactyly.

TS2 is diagnosed when a genetic test identifies an amino acid change of G406R in exon 8 (not 8A). It is identified at birth if an infant presents with very serious cardiac concerns or hypotonia, but no syndactyly or other physical anomalies.

I think sadly we are perhaps losing a number of TS2 babies due to LongQT heart rhythm not being identified soon enough. If only newborn screening included a simple LongQT check or the blood spot screening included CACNA1C in addition to the nine rare but serious health conditions they currently look for.

ATS (Atypical Timothy syndrome) is diagnosed when a genetic test identifies a pathogenic variant of the CACNA1C gene different to those that cause TS1 and TS2. It is often identified at birth if an infant presents with a multisystem health concern that usually includes cardiac and hand anomalies.

Calvin is an Atypical but if there are no health concerns or syndactyly present at birth, as in Calvin’s case, these ATS children don’t get diagnosed until much later in childhood, either as a result of an ‘event’ or because their genes have been sequenced in an attempt to diagnose the reasons behind their developmental difficulties.

When did you realise your son Calvin had the condition?

In our case Calvin didn’t speak until his first year at school and then it was only by using Makaton, something I’d taught him. After having fought to get him assessed, he was eventually diagnosed with developmental verbal dyspraxia (DVD). Calvin also has developmental delay with language, learning and social communication difficulties, and he shows autistic and ADHD-like symptoms but hasn’t received a specific diagnosis of either. In 2016 when he was nine years old, the Deciphering Developmental Disorders (DDD) study found the change in the CACNA1C gene; this was backed up by the 100,000 Genomes Project in June 2019.

We were told of the gene change just as Calvin was about to start specialist school following a long battle fought with the local government – a fight I firmly believe would have been easier had we had a diagnosis of some sort at the time. Following an ECG Calvin was confirmed as having a Long QT heart rhythm and, in December 2016, Calvin had an ajmaline provocation test to rule out Brugada Syndrome and a cardiac monitor implanted which uploads heart data to the cardiology team at Bristol Hospital every night. This was all really scary, especially as we hadn’t known he had anything wrong with his heart.

There are 10 families that we know of in the UK with these three types Timothy Syndrome and for the Atypical children the timelines are similarly frustrating with regard to diagnosis delay. 

The journey as a family has been pretty tough; having no diagnosis and fighting the system for help and support; to be told that we may just have to accept that we may never know what is happening; to digesting the news of a new health complication and a gene change so rare that no one knows the answers anyway.

As it is a rare disease, how have you found the general understanding of medical professionals towards Calvin’s symptoms? Were you forced to look elsewhere to find information about the condition?

In our experience, and one of the reasons why we need to raise awareness, there seems to be no holistic approach and very few answers. For example, Calvin is one of the TS children with fluctuating temperatures – he can be as low as 35°C or high at 39.5°C and apparently totally fine in himself – but, despite prodding, probing, overnight hospital stays and cultures grown, the outcome on his file says ‘temperature instability – likely related to the gene mutation’ and no one can say why.

Personally, I think it’s something to do with his hypothalamus which would also explain his frequent headaches too, but who knows? Medical professionals have very little information about Timothy syndrome, it is just all too rare in the world of rare. There are no information sheets or handouts, and so newly diagnosed parents are left with no choice but to turn to the internet to learn more and to find answers. It’s then that you start reading that the average lifetime expectancy is 2.5 years and that fewer than 100 patients have been reported with this disorder worldwide.

The learning curve as a parent of a child with Timothy Syndrome is very steep and the need for information in great – I even found myself attending a New Scientist one-day Masterclass in Genetics event in London in 2017 in an attempt to understand more. I know so much more than I did but I still don’t know the answers. I know that there are around 43 living patients with Timothy syndrome in the world and our oldest living is 28 years old.

Have you been able to connect with others who live with the condition?

On diagnosis I turned to the internet to find and learn more. Through SADS (Sudden Arrhythmia Death Syndrome) UK I managed to get an email address for Katherine Timothy. Timothy Syndrome is named after Katherine Timothy who first described the condition. While conducting a study on Long QT syndrome, Katherine identified a very small subset of infants who had extremely prolonged QT intervals and always presented at birth with syndactyly or conjoined fingers and toes. The DNA of these children was collected and entered into every possible genetic study for almost 20 years. In 2003, the discovery was finally made.

I wrote to Katherine and found that not only was she the most remarkable lady but she has also personally communicated with the parents of most of these TS children, and continues to include them in her ongoing studies while working with other medical and scientific investigators to better understand Timothy Syndrome.     

I also found a Timothy Syndrome support group on Facebook which was amazing as it meant I could speak with other families, although, it was heart-breaking as there were so many bereaved families. I have twice travelled with Calvin to America to attend the SADS Foundation conference. On the first occasion there were six TS families at the conference and at the second there were 10. Having virtually met them already on the Facebook group, they instantly felt like family. I learned that there were many common symptoms with our children and the strength from being together, sharing experiences and understanding is overwhelming.

I still had more questions than answers and it was becoming clear to me that if awareness of this ultra-rare disease was not increased we were unlikely to be the subject of any research that would give us the answers. I also knew from my experience in America that I needed to bring TS families together. I registered Timothy Syndrome Alliance (TSA) in the UK as a charity in September 2019, completed the Building Rare Communities Project with Genetic Alliance UK and began studying for the Chartered Institute of Fundraising Certificate.

I worked with the Neuroscience and Mental Health Research Institute and in December 2019 they hosted our first Timothy syndrome family day. The day was a huge success and featured talks from international researchers and clinicians working with Timothy Syndrome and CACNA1C variants, including Katherine Timothy herself. It offered families from across the world an opportunity to come together and share their experiences. Eight TS families from England, Scotland, Wales and Dubai met for the first time ever. We experienced tears, joy, friendship, learning and hope. The next proposed date for a Family weekend is in 2021.

Calvin has taken part in studies and research projects tied to his condition. What did this mean to you and Calvin?

In March 2019 we were invited to go to the University of Cardiff to take part in the IMAGINE ID Study, a research project studying the long-term behaviour and mental health of children and young adults with intellectual disability where there is a genetic cause. This is where we first met Professor Jeremy Hall and his team at the Neuroscience and Mental Health Research Institute. This was all very exciting as their interest in the CACNA1C gene was as great as ours – bloods were taken too to create an iPS Calvin brain.

We kept in touch and it was with their amazing support that we pulled off the family day. It was through this day we met Elizabeth Tunbridge, Associate Professor at Oxford University who also has an interest in TS and what CACNA1C molecules are present in human brain tissue.

We are thrilled to have their support in contributing to our new website that is under active construction at the moment thanks to a volunteer we found through MediaTrust. When we have this website finished it will transform TSA. We will be able to virtually hug newly diagnosed families with information and some answers and direct them to our support group, we will be able to educate the medical community, drive research and clinical development to enhance scientific understanding, raise funding and a supporter base to help us do this and help save lives of children with Timothy Syndrome.

In a bid to raise awareness on the condition, you and Calvin have made a film. Can you tell us about this experience and why you believe it’s so important?

With so few of us TS families and no established social media outlet, I decided the best way to raise awareness was to produce a short film to introduce people to Timothy syndrome and to tell some of our stories. We did this with the help of a long-time friend who has a passion for film making and a drive to inspire. The film shows that whilst the TS children are all different their journeys, which began with confusion, loneliness and self-dependence led to discovery, diagnosis, friendship and hope, have all been similar and the need for community is clear. We have found a few more families whilst I have been on this journey, one even found us via the awareness film, which is amazing.

I entered the film into Rare Disease UK’s Rare Film Festival in February and we were honoured to win the award for ‘Best Aspiring Filmmaker – Voluntary Group Collaboration’. The film also received official selection for Disorder: The Rare Disease Film Festival. After the festival was postponed due to COVID-19, the film was added to the Disorder Channel on Amazon Fire and Roku this summer to bring rare disease films directly to people’s living rooms. Expanding on our audience we are also finalists in the ‘Healthcare Charities and Patient Associations’ category at the PM Society Digital Awards that takes place this next week on Wednesday 16th & Thursday 17th September.

The film can be watched here: https://vimeo.com/382596609, and by sharing this film you can help us continue to raise awareness and drive people to our new website when launched for more information.  

What’s on the horizon for Calvin and yourself with regards to his condition? What are your hopes for the future?

For Calvin and the TS families I need to continue to create interest in TSA, particularly from the medical and research communities. I also need the journey to be smoother with less feelings of isolation for families with a new diagnosis of TS. We are slowly getting information out there, for example we now have information leaflets available to signpost families to us on the Unique and Contact a Family websites (who are the two main support groups families tend to turn to with a new diagnosis) and of course we will soon have our new website ‘live’ too.

Excitingly both Katherine Timothy and Andy Golden (NIH) are about to start our Natural History study to track the course of TS over time by examining patient demographics, genetic differences and other factors that are related to the disease and its outcome. This will allow for the development of disease management guidelines by identifying key factors and the touch points of diagnosis.

To link with this we are also creating a worldwide Timothy Syndrome patient registry, a major determinant for successful translational research into Timothy Syndrome. Understanding the subtitle changes between the differing mutations will give a greater understanding of the function of the CACNA1C gene at large and may achieve some answers for our TS children.