Life with a rare condition – why community building is so important

My name is Sophie. My son, Calvin, is 15. Like many young people his age he enjoys Pokémon cards and pepperoni pizza. His favourite subject at school is art. He loves cuddling with our two dogs, Toast and Bean.

But, unlike most of his peers, Calvin is navigating life with a genetic condition – a rare CACNA1C variant. As his mum, it’s incredibly important to me to understand how this gene affects my son. I need to know how I can best support him, particularly regarding his healthcare and education, and prepare for what the future may hold so he is as happy and healthy as can be. I know I’m not the only one in our CACNA1C community looking for answers. We all are.

What is CACNA1C?

CACNA1C is a gene that provides the code for a protein found in cells throughout the body. This protein manages the movement of calcium in and out of the cell, which is critical for many cells’ functions. Changes to the gene can cause changes to the protein and its ability to manage calcium movement, making it work more, less, or not at all.

If CACNA1C has ever been on your radar then it’s most likely because of Timothy Syndrome (TS), a multisystem disorder caused by a particular variant in the CACNA1C gene that presents notably with a prolonged QT interval – meaning that the heart takes longer to ‘recharge’ between beats which can lead to an irregular heartbeat rate or rhythm. It’s ultra-rare, with less than 100 known individuals living with the condition globally and can quite easily be missed unless the webbing of fingers and toes (a high prevalence indicator of Timothy Syndrome Type 1), hip dysplasia (common in Timothy Syndrome Type 2), or an unusual heart rhythm is picked up by a knowledgeable or inquisitive healthcare professional leading to genetic testing. Sadly, due to the rarity of Timothy Syndrome, genetic testing is normally only undertaken as a result of a cardiac event rather than pre-event.

There are other symptom indicators, including epilepsy or seizures, hypoglycaemia, neurodevelopmental symptoms, gastrointestinal concerns, and decreased muscle tone, to name a few, but these could be indicative of so many other diseases and disorders they don’t shout out CACNA1C on their own. And then there are the not-so-well-known CACNA1C variants, the ones other than the one known to cause Timothy Syndrome. These newly characterised rare diseases are called CACNA1C-related disorders and can also present with multisystem symptoms, some seemingly with just prolonged QT known as LongQT8, and others with no cardiac symptoms at all but a whole myriad of neuropsychiatric symptoms such as autism spectrum disorder, seizures, and attention deficit hyperactivity disorder. You can find out more here.

Calvin’s story

Calvin has one of these not-so-well-known CACNA1C variants – a diagnosis which took almost a decade to receive. Calvin is my second son, and from a young age I could tell he was developing differently to his older brother. He wasn’t hitting the milestones you’d expect and was late sitting, smiling, and babbling. At age 6 he was enrolled on a UK study called Deciphering Developmental Disorders in the hope it may provide an answer to the challenges he, and we as a family, were facing. Specific genetic tests for diseases such as Angelman Syndrome and Fragile-X had already come back negative. He had a severe speech and language delay, and we were using Makaton, a unique language programme that uses symbols, signs and speech to communicate and understand the most basic of needs such as ‘hungry’, ‘thirsty’ and ‘more’. The Speech and Language Therapist had confirmed he had a rare speech condition called Developmental Verbal Dyspraxia (difficulty in making and coordinating the precise movements needed to produce clear speech with their mouth) and this was also most likely responsible for his excessive drooling. He also had hypotonia and abnormal involuntary movements (tics and stereotypies).

Getting answers

It took another 4 years to get any results, by which time he was also presenting with intellectual disability, incoordination, attention deficit hyperactivity disorder, anxiety, autistic symptoms, oppositional defiant disorder, poor sleep, weird temperature fluctuations, and he still wasn’t toilet trained. We had just finished our battle with our local authority to get him into a specialist school when we were informed by letter of the gene change and the need for all three of my children to have an electrocardiogram (ECG) to check their heart rhythm and electrical activity. Calvin was found to have a borderline prolonged QT interval. At that time his variant was classified as a Variant of Uncertain Significance (VUS). Worryingly there is so little published on CACNA1C-related disorders that individuals are frequently classified as having a VUS, which basically means the genetic testing laboratories who decide if the gene is disease-causing or not simply do not know if it is or not. As a result, families and individuals may not even be informed of the findings, leaving them to continue their diagnostic odyssey with symptoms but no professional support or community to lean on.

We were in an advantageous position of knowing the gene because we had been on this study and the 100,000 Genomes Project confirmed the findings. There was a frustrating lack of information on the internet, so Calvin and I travelled twice to the USA to meet some of Timothy Syndrome families (there were 43 living known individuals with this gene change at this time) and Katherine Timothy (after whom Timothy Syndrome was named) who I’d found as a result of my research. At that time as there were so few of us with these not-so-well-known variants it was called ‘Atypical Timothy Syndrome’, now known as a CACNA1C-related disorder. I still had more questions than answers, particularly regarding Calvin’s neurological issues and it was becoming clear to me that if awareness of this ultra-rare gene did not increase, we were unlikely to be the subject of any research that would give us the answers.

Building a UK community

I registered Timothy Syndrome Alliance (TSA) as a charity in September 2019 to increase knowledge and understanding of the condition and grow our CACNA1C network. We are now a growing community of over 120 individuals known to have this gene change. We have a Scientific Advisory Board and a CACNA1C Community Registry and through recent studies with our CACNA1C community, we know that individuals identified with CACNA1C-related disorders should be screened and monitored for a broad spectrum of neuropsychiatric symptoms throughout their lifespan in order to properly diagnose, treat, and support maximal development (Levy et al.). Six years after getting the genetic report for my son Calvin, his not-so-well-known variant has also been reclassified as ‘Likely Pathogenic’, which means there is over a 90% certainty of this gene being the cause of his challenges. Through our amazing collaborations with researchers and healthcare professionals working on CACNA1C, we can also share the very latest knowledge on CACNA1C.

Collaborating with experts at Cardiff University

I met the Neuroscience and Mental Health Innovation Institute team, based at Cardiff University, through a study on which I’d enrolled called Imagine ID. I knew they had an interest in CACNA1C, with Professor Jeremy Hall’s lab studying the gene for almost 10 years. A collaboration was soon born, and by December 2019 we had our first Timothy Syndrome family day, bringing 8 families together for the first time. We have been working with the Institute ever since, and recently published our first paper, which is the result of international collaboration between the Cardiff University team (Dr Jack Underwood and Professor Jeremy Hall) and Stanford University (Dr Rebecca Levy and Professor Sergiu Pașca).  I was delighted to be invited to speak at the Institute’s launch event in May, and had the opportunity to forge new research connections and raise awareness of the work TSA is undertaking.

Timothy Syndrome Family Day – December 2019

About our ‘Connect CACNA1C Global Network Conference’

Our virtual, language-accessible, ‘Connect CACNA1C Global Network Conference’, hosted by the Neuroscience and Mental Health Innovation Institute, is an opportunity for CACNA1C individuals, families, caregivers, researchers, scientists, healthcare professionals, advocates, and supporters to come together. By collectively sharing current knowledge, and ongoing studies, exchanging ideas, and fostering collaborations we can help shape the future of CACNA1C research, improved diagnosis, and care.

Our community is worldwide so by embracing this digital platform and using an AI language translation service (Wordly), we ensure that everyone, regardless of their geographic location, has the opportunity to join. We are grateful to the Stanley Grundy Foundation for providing us with the funding to host the conference in this accessible way for our international audience.

Together we are raising the profile of CACNA1C and driving advocacy and research forward.  We are empowering CACNA1C through collaboration.

About the author: Sophie Muir is the Chair of the Timothy Syndrome Alliance (TSA)