Sophie Muir is a loving mother of Calvin, a 15-year-old boy having a rare CACNA1C-related disorder. Having gone through fire and water and not finding answers to her questions, she registered a charity (Timothy Syndrome Alliance) in the UK with the goal to make a difference in the lives of those affected by CACNA1C-related disorders worldwide.
Sophie believes that raising awareness, educating health professionals, supporting research, and bringing together families, clinicians and scientists are the keys to finding a treatment and cure for CACNA1C patients.
Sophie, how did you come to realize that Calvin has a CACNA1C-related disorder?
Well, actually I’ve got 3 boys. My oldest is 17, my middle one is 15 and my youngest is 11. So, when Calvin, my middle one, was born there was just that kind of ‘know as a mom that something’s not right’ feeling. He had late milestones, so he was late sitting, he didn’t talk till he was 7, he had continence problems, hypotonia, didn’t babble, late smiling… they eventually had him tested for the obvious like Fragile X Syndrome, but then I had to push the geneticist to do more. That was coincidentally at the same time as the DDD study (Deciphering Developmental Delay) that was specifically looking at the genetics of children with developmental delays.
We enrolled on that study when he was about 6 and just before he was 10 we got a letter to say that he had a Variant of Uncertain Significance (VUS) in the CACNA1C gene. You know, there are guidelines for the geneticists to classify different variants. In the UK it’s the Association for Clinical Genomic Science (ACGS) guidelines and so when the labs and geneticists look at a variant, they look at wide ranging evidence and classify the finding as Pathogenic or Likely pathogenic (disease causing), a Variant of Uncertain Significance (VUS) or at the bottom of the table there’s Likely benign and Benign (non-disease causing). Because there was very little information on my son’s variant they classified him as a VUS. That was hard because it meant that we were still on our odyssey. Nobody would confirm whether it was the cause of his difficulties and symptoms but me being me I wanted to know more.
At that time though (2016), nobody could give me any information so I looked on the Internet and found that the gene itself was linked with Timothy syndrome.
But Calvin wasn’t diagnosed with Timothy syndrome. Is it because his variant wasn’t previously associated with this disorder?
Yes, Timothy syndrome is caused by G406R variant, whereas Calvin has a different variant. So you’ve got Timothy syndrome type 1 (TS1) and 2 (TS2) depending on whether it’s exon 8A or 8 of CACNA1C. The difference is that TS1 will have syndactyly (webbed fingers/toes) whereas TS2 tends to have hip dysplasia, both will present with prolonged QT. But everything is multisystem with regard to symptoms because the calcium channel runs through the whole body. There’s a whole list of symptoms particularly on the neurodevelopmental side, then there’s hypoglycemia, cardiac, epilepsy, hypotonia…
And so even though Calvin hadn’t been diagnosed with Timothy syndrome I wanted to know more about it since it was the same gene and he presented with many of the same symptoms. I managed to get the email address for Katherine Timothy, who was among the first to identify and analyze this disorder and as such it was named in her honor. I emailed her and said: “Well, you know, we have this variant. And if we’re not TS1 or TS2, are we TS3? What are we?” And she said: “No, it doesn’t really work like that. You’re VUS, you’re an additional variant that’s been found in the gene and we don’t really know yet what it is.”
So I found out that there was a patient group under the SADS foundation (Sudden Arrhythmia Death Syndromes) in the US. There were a small number of Timothy syndrome families that would meet yearly so I booked a flight and I took my son to the States to meet Katherine and the other families. That was amazing! I very quickly learned that he had some overlapping symptoms with the Timothy syndrome kids, but we were still not classed as Timothy syndrome. We had no name.
Because I’d been dealing with all the neurological issues with Calvin growing up rather than the cardiac (which I knew nothing about until he was 10 and had an ECG) I felt that all the research was very heart-specific, there’d been nothing really on the developmental delays, the challenges of speech, the tics, etc. So, when I went back to the SADS Foundation conference for the second year I shared that I’d registered Timothy Syndrome Alliance as a charity in the UK with the aim to find answers.
At the same time I’d registered Calvin for some studies in the UK with a project called Imagine ID and that’s when I linked up with Cardiff University who were working on this study. We went to Cardiff University, and we gave some blood so they could grow some iPSC cells.
OK. So, you are collaborating with researchers from Cardiff University. Which group is that?
In fact, Cardiff University has been studying CACNA1C for about 10 years now and it’s an amazing team in the lab of Prof. Jeremy Hall at the Neuroscience & Mental Health Innovation Institute that we now collaborate with. They study how genetic risk factors influence the brain and lead to the development of neurodevelopmental disorders like schizophrenia or autism.
So, we went there and we gave some bloods. They were fascinated by us and as a family we were equally fascinated by them. I asked if they would work with TSA with their research and they agreed. I brought together the families in the UK for a conference at Cardiff in 2019 shortly after registering the charity. At that time there were 9 families that attended; some Timothy Syndromes along with these newly characterized CACNA1C-related disorders (CRDs). Katherine Timothy came over from the US to attend and that was really the beginning of what’s been a really exciting learning curve.
So we’ve got research running and the first paper from the study was published recently (see here). A great paper that is a result of international collaboration between the NMHII Cardiff University team (Jack Underwood, Jeremy Hall) and Stanford University (Rebecca Levy, Sergiu Pașca). They surveyed 24 CRD individuals to define their neuropsychiatric and developmental phenotype and what they found is that many of these individuals share multiple neuropsychiatric symptoms such as developmental delay, incoordination, hypotonia, autism spectrum disorder, seizures and attention deficit hyperactivity disorder and that there were no significant differences in symptoms in participants with and without long QT syndrome. They confirmed that CACNA1C plays a key role in brain development. Really lovely paper highlighting that there is a phenotype outside of TS1 and TS2 and the Long QT8s. It’s a very important step confirming that we need to acknowledge all the CRDs, not only Timothy syndrome and Long QT8s when identifying and classifying CACNA1C variants.
Along with this, we’re also in contact with other researchers, Universities and institutions working in this field. Thankfully researchers are interested in helping us raise awareness of CACNA1C and calcium channels and they understand the benefits for our community so it’s all very exciting.
It’s really good to hear that researchers are willing to collaborate, chat with patients and their families, and educate your community. So, how big is the TSA community now? And, do you have any estimates on how many CRD patients are there in the world?
We now have about 120 families in our support group, a mixture of TS1, TS2, Long QT8 and other CRDs. We are global, our community is all over the world; UK, US, China, Brazil, Australia… Unfortunately, not all families speak English as their first language so when I chat with them I have to use Google Translate. It’s challenging but it’s really important that these families and individuals can understand what we’re doing, what we’re finding and how we can help by working together. And so as we grow we are increasingly relying on translators to enable these families to understand where we are with regard to research and support – we shall be using translation for our online conference this coming June so it is accessible to everyone.
As to how many CRD patients there are in the world, I don’t think we have these estimates. One of our researchers said recently “Our best guess is there may be hundreds of people globally, but that could be thousands. There are tens of thousands of kids and adults with these features, and no-one has ever done genetic testing for CACNA1C on them, because they didn’t know to look.” With prolonged QT known to be associated with many CACNA1C variants we need to screen these individuals prior to a cardiac event and not because they have had a cardiac event.
Many of the CRDs that we know of are n=1 meaning they are the only individual identified in the world, but we are changing some of these to n=2 and n=3 as we grow, which is great. The challenge is that the CRDs are not being classified as likely pathogenic or pathogenic, many are being classified as VUS. In the UK, for example, if you are classified as a Variant of Uncertain Significance (because there is not enough evidence of pathogenicity) you are told that there is no genetic cause for the symptoms being experienced, and you return back to your community with symptoms that most probably led to the genetic testing in the first place. You end up in this diagnostic odyssey.
Some variants are reclassified to Pathogenic or Likely pathogenic over time and there are some VUS that are downgraded to Benign or Likely benign and so I understand we need to be mindful. It can be difficult for families that seek support based on a VUS and are later informed that the VUS is benign and non-contributory to the child’s medical/developmental condition.
That being said, given the increasing knowledge of this gene and the clinical importance of screening and therapeutically addressing neuropsychiatric and cardiac symptoms, individuals whose testing reports are most suggestive of a CACNA1C-related disorder (ie a ‘hot’ VUS according to the ACGS Classification chart) should, I believe, be notified as such on their genetic report so they may find and seek knowledge and support from our CACNA1C community. Additional testing or reanalysis can then be carried out at a future date and the variant reclassified as and when sufficient evidence.
This Christmas my son’s variant was reclassified as Likely pathogenic 6 years on from his original VUS classification. This is not only great for his health care and educational support but it also means that individuals identified with the exact same variant and phenotype that are identified will most likely be classified as Likely pathogenic too, especially as we now have structure/function studies for his specific variant.
This would help grow our CACNA1C community – the bigger we are the more we will learn. So, we know CACNA1C is an important gene and there are people out there, but we have to find those people.
And how do you find them?
We raise awareness. We really need to grow awareness of CACNA1C to find the CRDs. So, for example, we made a film about my own family experience. In fact, it’s our first award-winning film highlighting the challenges faced by families and emphasizing the importance of getting together in order to find answers. We have two films now, plus we are working on two more, one with NMHII highlighting the importance of engagement in research and the other will be aimed at HCPs to help improve diagnosis. I enter them into film festivals globally, post on social media channels and our website to widen our audience.
I’m putting out signposts from the charity all the time to help people find us. Everything I do I hashtag, I update other information sources where possible and collaborate and connect with those with an interest in the gene. Our Scientific Advisory Board is instrumental in this too.
For example, we have recently worked with Healx to create a CACNA1C-related disorder Wikipedia page which has been accepted and approved – a massive resource and validation for everyone – not only for CACNA1C families and individuals searching for knowledge but those who may be trying to support, learn and raise awareness, who find themselves investi-googling for information and signposting. Taking on Wikipedia has been on my to-do list for so long yet was so overwhelming I just didn’t know where to start (a bit like Tik-Tok!). The team at Healx nailed it! We now have an accurate and validated information source for the growing CACNA1C community to learn from and enhance with their own insights and citations.
We aim to raise awareness globally, but as I’m based in the UK, predominantly a lot of my work is advocating in the UK. For example, our applications were approved for CACNA1C to be included as a gene within the Genetic Epilepsy syndromes and Congenital hyperinsulinism genomic tests listed in the NHS National Genomic Test Directory (PanelApp). As PanelApp is an open platform this knowledgebase of evidence for gene-disease associations is used by the wider scientific community. My theory is that if I can spread the word of CACNA1C in the UK, over social media channels, through film and our website alongside our researchers, then this will ultimately, with the support of our community, spread globally. Our CACNA1C Community registry (on the Pulse Infoframe platform) which has been accepting participants since June 2022 also helps create interest, promote research and increase knowledge.
It sounds bizarre, but the lockdown as a result of the pandemic was a benefit for me with regard to running the charity. I’m in the country, I can’t go anywhere because I need to be here for my kids so the world kind of opened up for me with what I was doing because everyone turned to Zoom. There were many more opportunities for me to meet all sorts of people I wouldn’t normally have met and to chat with them. Every time opportunities to connect happen, another door opens, so along with a lot of hard work there has also been serendipity.
Along the way we collaborate with other rare diseases joining our efforts and making our voices that much stronger and louder. We recently started a new endeavor that we have called The VGCCC where we’re bringing together all the genes within the calcium channels.
VGCCC? I’ve never heard about it. Could you tell me more? Who’s involved? What’s the plan?
Collaboration is the way forward. If everybody works together we’re going to find answers…and that’s how the Voltage-Gated Calcium Channel Collective (VGCCC) came about. So, when I first got together on a Zoom call with the mums from the other calcium channel patient advocacy organizations and support groups we looked at what the existing authority type websites have listed as our phenotypes for our communities and compared them to what they are in reality. These websites aren’t up-to-date and are heavily reliant on published papers that are yet to be written for our genes. It is our patient groups that represent the patient voice and those of the families and carers living with this day in day out…and this is why the Collective will be so important.
The researchers need to know how our children and individuals are presenting and how many different overlapping symptoms there are with the different genes as there are links to be found. We need to keep researchers informed and support them because they’re the ones that are going to find the answers. And we can do it by bringing together researchers and families in a space where we can promote conversation.
The idea is not to focus only on our own particular genes (in my case it’s CACNA1C) but to work together as a channel so at the moment we also have CACNA1A, CACNA1D, CACNA1E, CACNA1F and CACNA1H. CACNA1A Foundation are doing brilliantly, they are bigger as a charity, they have more families, and they support research with grants. CACNA1H has just registered as a Foundation in the US. But if you look at CACNA1D, CACNA1E and CACNA1F, they don’t have that voice yet as a Charity or Foundation, they are small Facebook groups and so we need to help them have their voice heard and help them and us grow our communities as well.
We’re already signposting to each other and having great meetings with ion channelopathy and gene researchers showing this is going to work. We need to raise awareness of all of our genes. We need to raise awareness of the calcium channels. Thankfully the researchers are interested and love this idea too. We are a supergroup – watch this space!
I’m thankful to Sophie Muir for taking the time to talk with me and sharing her story and insights.
If you have questions to Sophie, you can contact her via LinkedIn: https://www.linkedin.com/in/sophie-muir/
If you want to support the Timothy Syndrome Alliance, please donate here: https://timothysyndrome.org/donate/
Pictures by Sophie Muir.