## **TIMOTHY SYNDROME ALLIANCE (TSA)** ## **A N N U A L R E P O R T** **FOR FINANCIAL PERIOD 1 DECEMBER 2020 TO 30 NOVEMBER 2021** **----- Start of picture text -----**
2021
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**www.timothysyndrome.org** **Charity Registration Number: 1185523** ## **WELCOME** ## **Vision:** Our vision is a world where shared knowledge and understanding lead to a cure for everyone with a _CACNA1C_ genetic variant. ## **Mission:** Our mission is to improve the diagnosis, treatment and care of individuals with _CACNA1C_ -related disorders, including Timothy Syndrome and LongQT8, and to support the families and carers of those diagnosed. ## **Our values:** Our values combine to form a solid foundation for the way in which we do things and what we believe in. We are **determined** , **supportive, empowering** and **a community.** _CACNA1C_ -related disorders, including Timothy Syndrome and LongQT8, do not have geographic boundaries. TSA has no boundaries. We support families wherever they are in the world. Why? Because we are # **strongertogether** 1 ## _**CACNA1C**_ ## **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’ function. 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. ## **What is Timothy Syndrome?** Timothy Syndrome (TS) is caused by specific changes to the _CACNA1C_ gene. There are two types of TS: TS1 and TS2. Most common symptoms include: abnormal heart function, irregular heart beat, abnormal heart structure, neuronal developmental delays, immunodeficiencies, endocrinological dysfunction, gastrointestinal concerns, effects on smooth muscle, effects on skeletal muscle, facial anomalies, syndactyly (joined fingers or toes), mild dental, skin, eye and hair anomalies. Some individuals have: significant episodes of low blood sugar levels (hypoglycemia), seizures, an unusually low body temperature (hypothermia). ## **What is a CACNA1C-related disorder?** A novel variant in the _CACNA1C_ gene - individuals have some but not all symptoms typical of Timothy Syndrome. Some affected individuals may present with multisystem health concerns that overlap entirely with Timothy Syndrome. ## **What is Non-syndromic LongQT8?** Non-syndromic LongQT8 overlaps with Timothy Syndrome in that the affected individual has LongQT (a prolonged QT interval on an ECG). There are many variants throughout the _CACNA1C_ gene that appear to cause non-syndromic LongQT8. 2 ## **ACHIEVEMENTS AND PERFORMANCE** ## **Raising Awareness** Our first **film** from 2019 continues to raise awareness and to signpost families to TSA to connect with the _CACNA1C_ Community for knowledge and support. Film festivals widen our audience; this year we were a finalist at the International Rare Disease Festival (Berlin) and Uno Sguardo Raro Festival – The Rare Disease International Film Festival (Rome). The film took Silver in the Best Creative Campaign category at the PM Society Awards 2021 (UK), whose audience is the pharmaceutical and healthcare industry. To coincide with Rare Disease Day on the 28th February we made a film called 'Rare Strikes Back' with aligned aims of improving knowledge amongst the general public of rare diseases whilst encouraging researchers and decision makers to address the needs of those living with rare disease. It signposts to both the TSA and the Rare Disease Day websites. The film was launched on all our social media channels and has been viewed over 11,000 times on Twitter alone. 'Rare Strikes Back' went on to win Best Storytelling by a Voluntary Group at the Rare Reach Festival - Rare Disease UK 2021 and Gold at the Charity Film Awards (UK) £0 - £100,000 Turnover Category. It won Bronze at the PM Society Digital Awards - Effectiveness Category, was a finalist at Uno Sguardo Raro 3 ## **ACHIEVEMENTS AND PERFORMANCE** Festival - The Rare Disease International Film Festival, QIFF: Quarantine International Film Festival (India)) and PM Society Digital Awards 2021 - Craft category. The film is also available on The Disorder Channel streaming through Amazon Fire and Roku. Our next film will be a deeper dive into _CACNA1C_ aimed at healthcare professionals. **'OPEN Health is a leading Global healthcare communications agency with extensive scientific expertise. It’s a pleasure to work with the team at TSA following their deserved award at the 2021 Rare Reach festival. It’s always wonderful working with a talented team that are collectively dedicated to better patient outcomes where there is such unmet need. OPEN Health are committed to providing expert pro bono resources to play a part in making this important and much needed film a success. Our role is to identify and validate the key clinical messages that the film needs to convey and create a script that makes both impact and mobilises healthcare professional into positive change. To enable this we have assembled a team of both scientific experts and project managers to ensure the film is scientifically robust, has the necessary impact and that we deliver on our promise.' Gavin Jones | Global Advisor | Rare Diseases** The TSA **website** continues to grow and is now available in the German language via a simple flag click. Our presence on **social media** forums such as Facebook, Instagram, Twitter and LinkedIn also show steady growth in supporters. With repeated use of hashtags we were delighted when a new family found us having seen **#CACNA1C** on Rare Disease Day. #TSAwareness21, our first **awareness day** was successfully celebrated on 1st October with many posts shared globally as well as awareness support from Congenica, Rare Revolution and Genetic Alliance UK. 4 ## **ACHIEVEMENTS AND PERFORMANCE** ## **Community** Timothy Syndrome Alliance (TSA) and the Neuroscience and Mental Health Research Institute (NMHRI) hosted online the Brain Research **Conference** online on 25th June 2021. The conference gave over 70 registered attendees 4 hours of the latest insight into _CACNA1C_ research delivered by seven leading figures in this field. A worldwide attendance saw families with TS or _CACNA1C_ gene variants and researchers drawn in from as far east as Malaysia to as far west as California. **"It’s a great privilege to be able to host the TSA annual meeting again. These events offer an opportunity for families with this rare disorder to come together from around the globe, make connections and hear about the** ## **latest advances in understanding it." Dr Jack Underwood Wellcome Trust GW4-CAT Clinical Research Fellow, NMHRI** The conference began with a talk from Gemma Wilkinson, who discussed using patient-derived calls to investigate _CACNA1C_ . Talks throughout the conference focused on research within _CACNA1C_ , including a session from Dr. Underwood, before a concluding discussion from Dr Rebecca Levy. Questions from attendees were taken in between talks, sparking in-depth conversation and constructive interaction between speakers and guests. **“The Brain and TSA research conference was wonderful, with four hours of the newest research information on CACNA1C and Timothy Syndrome shared. I’ve waited for years for researchers to study neuronal issues observed in TS in-depth and I’m very pleased with the collaborative efforts now being undertaken with Dr. Jeremy Hall and his associates, Dr. Liz Turnbridge and the Stanford University group.”** ## **Katherine Timothy** Dr. Underwood highlighted, “Meeting the families and hearing their thoughts and hopes provides meaning to our research, and is leading to discussions, partnerships and international collaborations among researchers investigating TS and CACNA1C-related disorders.” 5 ## **ACHIEVEMENTS AND PERFORMANCE** Every session of this conference was **transcribed and translated** into Brazilian Portuguese to ensure the information was accessible to our families. ## **Early and accurate diagnosis** TSA has submitted an application via NHS England and NHS Improvement to update the 2021/22 National Genomic Test Directory. The application is to update the nomenclature to include ' _CACNA1C_ -related disorders' on existing panels and to include _CACNA1C_ on a new panel 'Early onset or syndromic epilepsy'. The Genomics England PanelApp, a publicly-available knowledgebase used by experts throughout the worldwide scientific community relates to genomic tests listed in the NHS National Genomic Test Directory. Clinicians and other healthcare professionals use PanelApp to view and interpret a panel that has been applied to their patient and to look at the evidence for the inclusion of a gene(s) in their patient report during a Multidisciplinary Team (MDT). If successful these changes will make a difference to improving early and accurate diagnosis. ## **Research and education** In October 2020 TSA entered The Student Voice Prize, an annual international essay competition that raises the profile of rare disease within the medical field, particularly with medical students, nurses and scientists who may have never come across rare diseases in their training. We worked with our amazing student Zoe who has been a TSA advocate ever since and even translated our website into German. Our German based families have also now worked with Zoe participating in a rare disease neonatology and paediatrics university scheme. TSA were delighted to be invited by Cambridge Rare Disease Network (CRDN) to take part in the inaugural Patient Group and Industry Partnering event. This event brought together 10-12 rare disease patient groups alongside a similar number of companies working in the orphan drug space with the 6 ## **ACHIEVEMENTS AND PERFORMANCE** goal of finding new avenues for collaboration between individual companies and patient groups towards the development of new treatments. A dissertation study looking at the psychosocial impact of living with _CACNA1C_ /TS/LongQT8 diagnosis has begun for a MSc Genetic & Genomic Counselling student we are working with at Cardiff University. Recruitment of _CACNA1C_ families has begun for the first international study investigating the effects of _CACNA1C_ variants on brain development and mental health (Cardiff University and Stanford University). We look forward to better understanding _CACNA1C_ as a result of this collaboration. We are working with Cardiff University on The Rare Disease Research Journey project which aims to create a short film with global reach showcasing the importance of public engagement in research, and the research journey from an individual’s involvement through clinical research to changes in practice and understanding. The project is a collaboration between the Neuroscience and Mental Health Research Institute (NMHRI) and TSA, with combined academic, charity and public involvement in production. 7 ## **ACHIEVEMENTS AND PERFORMANCE** In September we ran a campaign on our social media channels which was successful in signposting new LongQT8 families to our support group. ## Published papers of note: Bauer, R., Timothy, K. and Golden, A. (2021). Update on the Molecular Genetics of Timothy Syndrome. Frontiers in Pediatrics, 9. https://doi.org/10.3389/fped.2021.668546 Rodan, L. H., Spillmann, R. C., Kurata, H. T., Lamothe, S. M., Maghera, J., Jamra, R. A., Alkelai, A., Antonarakis, S. E., Atallah, I., Bar-Yosef, O., Bilan, F., Bjorgo, K., Blanc, X., Van Bogaert, P., Bolkier, Y., Burrage, L. C., Christ, B. U., Granadillo, J. L., Dickson, P., … Shashi, V. (2021). Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations. Genetics in Medicine, 1–11. https://doi.org/10.1038/s41436-021-01232-8 ## **Support** ## **'having the TSA Facebook group has helped massively in understanding that we aren't alone in this, and that we all can support each other even at a distance.'** TSA administrates an online Facebook Support Group for individuals and families of _CACNA1C_ -related disorders including Timothy Syndrome and LongQT8, offering 24/7 access to emotional and practical support and information via our families. The benefits of this are huge, enabling: meeting and befriending other people with the same rare disease and similar experiences from across the world 8 ## **ACHIEVEMENTS AND PERFORMANCE** learning about the disease giving and receiving emotional support having a place to speak openly about the disease and one's feelings - learning coping skills feeling empowered and hopeful - advocating to improve healthcare. ## **'like minded people who don't judge and are always there if you have a lot of questions'** The support group is growing in size as is the spectrum of affectedness as we find more families. Identified previously as a need, TSA began Support Each Other ‘drop in’ Zooms which were well attended. This support has now progressed to working with Rareminds which is an organisation that specializes in providing counselling and emotional wellbeing services for the rare disease community. ## **'Not being alone is a tremendous help.'** Sometimes other forms of support can help our community. Donations have enabled cardiac equipment – a defibrillator – to be donated to a family and, sadly, contributions have also helped another family towards unexpected funeral expenses for their child. ## **'Just beyond wonderful to be connected with other families.'** ## **Fundraising** ## **'I feel seen (you see us as others cannot)'** Every donation we receive goes to help fund the vital work that we do as a charity. We: support and connect the _CACNA1C_ community improve _CACNA1C_ diagnosis, outcomes and quality of life support _CACNA1C_ research initiatives The impact of the pandemic accompanied by low awareness of rare diseases and TSA makes fundraising a challenge however by widening our digital reach and using creative ways to engage audiences we are continuing to connect and 9 ## **ACHIEVEMENTS AND PERFORMANCE** actively grow our support base. We have only one volunteer managing TSA full time which means the amount of time available to specifically fundraise is limited due to the other mission based activities. The generosity of your support has been amazing. Whether it be regular monthly donations, a one off gift, creating a birthday fundraiser on Facebook or sponsorship from running a marathon our heartfelt thanks goes to each and every one of you. ## **'TSA is the conduit of all the advances in medical research, care, and quality of life support.'** Special thanks to the following for your support and projects: Limestone Media, the teams at the NMHRI Cardiff University, Department of Psychiatry, Oxford University and Stanford University, OPEN Health and Charity Translators. Dmitry Kran, Zoe Shaked, Bhavna Vadukul and our students Tali Feen, Laurel Mangelsdorf and Raivat Shah from Muhlenberg College. 10 ## **TIMOTHY SYNDROME ALLIANCE (TSA) TRUSTEES' REPORT General Information REGISTERED CHARITY NUMBER: 1185523** TRUSTEES: Nick Muir **The trustees present their report for the period 1 December 2020 to 30 November 2021.** Katherine W Timothy (Appointed 14 December 2020) Andy Golden (Appointed 14 December 2020) Sally Johns (Appointed 8 September 2021) REGISTERED OFFICE: **Objectives:** To relieve the needs of those affected by _CACNA1C_ -related disorders including Timothy Syndrome and LQT8, their families, friends and carers. Promote greater understanding of the causes, symptoms and treatment. Raise public awareness of the symptoms, needs and related medical conditions. **Structure, governance and management:** Timothy Syndrome Alliance (TSA) is a registered charity number 1185523, governed by the Charities Act 2006. The charity is a Charitable Incorporated Organisation registered on 27 September 2019 under the Foundation Governing Document. New trustees are appointed by the serving trustees, considering the skills required by the board. **Public Benefit:** The Trustees confirm that they referred to the Charity Commission's general guidance on public benefit when reviewing the Charity's aims and objectives for the year. Public benefit has been achieved as per the activities outlined in the Achievements and Performance section of this report. Trustees' responsibilities statement The trustees are responsible for preparing the trustees' report and the financial statements in accordance with applicable law and United Kingdom Accounting Standards (United Kingdom Generally Accepted Accounting Practice). The trustees are required to prepare accounts for each financial year, which reflect the receipts and payments of the charity and of the surplus or deficit of income against payments for the year. ## **The trustees are responsible for:** • keeping proper accounting records which disclose with reasonable accuracy at any time the financial position of the charity; and • safeguarding the assets of the charity and hence for taking reasonable steps for prevention and detection of fraud and other irregularities. 13 July 2022 The trustees annual report was approved on ........................ and signed on behalf of the board of trustees by Sophie Muir Chair of Trustees 11 CHARITY COMMISSIO FOR ENGLAND ANO WAIE Tlmothy Syndrom• Alllanc• 1185523 Recel ts and ments accounts CC16a To Section A Receipts and payments Unrestricted Endowmont furm lund• toth• I￿•41 £ t•thi Mw••t £ tolts r*w••t £ tr•th• r*w••t£ tDth• fi•w••t£ Re5trictod La•t y• A1 R•c•lpts Volun¢ary RecthFIs AR) Tot•1 rncelms 084 AJ P•¥m•nl• 3127.8 128 Govefnonc• c￿1$ Sub ￿£￿1 3.226 Sub total 3,228 3.226 Net of recwptsl(paymentsJ A6 Trn￿l•rn b•twMn lund• Cmh fvnd• l•*t >*•r •nd Cash funds Ihis year end 1858 2,858 1858 2.858 12 Séctlon B Statémént of asséts and Ilabllltles at the énd of the perlod Unro6trict8d funds Endowm&n¢ funds IuDd* Iw fvnd• nd• fvnd• D•iails B4 A•••ts r•t•ln•d for I ¢h•rlty• 4 Details 85 U•t41111•• Dql• 17 March 2022 13