Creatine Decoded: The power of patient registries and patient-led research initiatives – How CCDS Families and Caregivers Can Drive Research

Creatine Decoded: The power of patient registries and patient-led research initiatives

How CCDS Families and Caregivers Can Drive ResearchCreatine Decoded: The power of patient registries and patient-led research initiatives – How CCDS Families and Caregivers Can Drive Research

#CreatineDecoded is a quarterly educational essay series that sheds light on research relevant for Cerebral Creatine Deficiency Syndromes (CCDS). The essays and interviews feature community contributors, often parents, who with the help of the ACD, explore in their own words the CCDS science you want to know more about.

This interview is brought to you by Kirsten Wiebe, Science Writer at the University of British Columbia, Dr. Sylvia Stockler, MD, University of British Columbia, and Sofia Balog, ACD Patient Registry Coordinator.

Have a topic in mind? Send suggestions to Laura Trutoiu, ACD Director of Research

ACD’s Scientific and Medical Advisor, Dr. Sylvia Stockler, published an article that describes how high-level evidence for new therapies can be accelerated through alternative trial designs, the development of standardized core outcome sets, international rare disease registries, and patient-led research initiatives.

Her work inspired the following Creatine Decoded interview; we wanted to speak with Dr. Stockler about how, through our organization and patient registry, we at ACD can help accelerate the development of therapies for inborn errors of metabolism like creatine deficiencies.

Dr. Stockler, thank you for your time. Please tell us about your background and how you got started in CCDS research.

I was trained initially as a pediatrician. I sub-specialized in Biochemical genetics, and also in neurology. All of this taken together brought me to CCDS research. In the 1990s, as a neurology fellow, I was in charge of a two-year-old patient who had unexplained developmental problems, an odd movement disorder, and basal ganglia changes without a clear diagnosis. This turned out to be a serendipitous opportunity for us to use magnetic resonance spectroscopy of the brain, which was at the time new technology and only available in the research setting. We realized this patient had no creatine in the brain at all. This was surprising to all of us because while we were all very familiar with many biochemical pathways, we did not know much about creatine pathways and creatine metabolism. It was through this that we discovered a new creatine deficiency syndrome, GAMT deficiency. Within a short time, more patients with GAMT deficiency were diagnosed, and we started thinking about how we could treat these patients. We initially started by providing a creatine supplement with the aim to correct its deficiency, but soon understood that we also had to find ways to reduce guanidinoacetate which accumulates in GAMT deficiency. Protein restriction in the diet and supplementation of ornithine have proven effective to achieve this latter goal. Soon after the discovery of GAMT deficiency two other creatine deficiencies were discovered, Creatine Transporter Deficiency and AGAT deficiency.

What is your current research on CCDS?

I am blessed to collaborate with Dr. Peter Axerio-Cilies, a UBC-based researcher on creating a drug repurposing pipeline, from lab-based drug screening to bringing candidate drugs to the patients. Peter is an expert in virtual drug screening and in validating the efficiency of drugs in the lab setting for Creatine Transporter Deficiency. My part is to develop an experimental setting where we would be able to treat children in a clinical setting with candidate drugs that Peter comes up with. I am particularly interested in the so-called n-of-1 trial design, which allows the creation of high-quality evidence about the efficacy and safety of a new treatment in single individuals. Assessment of outcomes such as seizures, behaviors, and movement disorders in repeated cycles on and off the therapy, will show how effective the new drug is and whether it should be tested in larger trials involving many more patients. The beauty of the N-of-1 trial design also is that we can measure outcomes that are important to single patients. We call such outcomes patient meaningful outcomes (PMOs). One of my master students, Delia Apatean, is currently working with the ACD on a proposed research project to develop a set of PMOs for Creatine Transporter Deficiency. This important work will further inform the design of n-of-1 trials as mentioned above.

I am also fascinated by all the activities ACD has launched as a patient/family organization and by the way they collaborate with physicians and scientists. I am particularly impressed by ACD’s efforts to establish a registry for CCDS (

Why are registries relevant to rare diseases and drug development?

The registry itself is important because it helps us to understand what kinds of symptoms, signs, and problems each patient has and how they evolve over time. Registries are the best source to help us understand what the patients’ main needs are, and from these to find treatments that meet these needs. Registries also help us to understand problems individual patients might have, problems that are perhaps not widespread but that are shared by a subgroup of patients with a certain condition. We want to understand these symptoms and signs because they might be very important outcomes for particular children. We want to be able to help individual patients. Registries inform clinical trials as you can get information from the registry about the natural history of the specific condition and about outcomes that are really important, really relevant for the disease.

What are registry-based trials?

Well, this is a very new concept. Registry-based trials go even further because in registry-based trials you actually get to use the pre-collected data of these patients in your trial; you engage these patients in clinical trials via their information. Based on the information that has been accumulated in the registry, the investigator can check which of the patients would meet the inclusion criteria for a new trial and approach them if they would like to participate. So, in this way, registries provide researchers with a never before available database of potential research participants. Moreover, once a clinical trial has been completed, the results of the clinical trial become part of the registry. This allows future clinical trials of the same disease to use the information from previous trials. Registry-based evidence means that you have a very stable cohort of patients available for outcome research and clinical trials. It allows us to continuously collect information about a patient’s condition within the same platform and in a streamlined way.

Why is it important for families to join the CreatineInfo Registry?

It is so important for every family impacted to join. First of all, they will glean for themselves a community. Secondly, and this is also an extreme benefit of the registry, information is not unidirectional. You get immediate feedback! For example, once you complete a questionnaire there are functions in registries that let you know how many other people with the same condition have the same symptom. If, on the other hand, you find that no one else has the symptom you describe, you can consider that you are perhaps an outlier, which is an exceptional way to contribute to knowledge! Or, you can perhaps consider that the symptom that is not shared by others with the same disease is in fact related to something else – perhaps you can explore other avenues for this specific symptom.

In your article “Developments in evidence creation for treatments of inborn errors of metabolism” you mentioned, “During the past decade, the patients’ role in orphan drug development has evolved from end‐users to active participants in research.” :
How can we, patient-led organizations, help you, researchers, to find better treatments and potential cures?

Well, this is exactly what you guys in ACD are doing! You are taking the initiative to create your own research capacity. You are helping us a lot because you tell us what is and is not important. This is the main goal of every research study – to resolve the problems that are important to the patient! Often we as researchers do not know exactly what is really important for the patient, we can just see what we can measure. These measurements are surrogates of what is important, but they do not tell us what exactly is important, what exactly makes a difference for patients.

Is there anything you wanted to add to this conversation?

We are currently living in exciting times with huge interest in rare diseases with treatments being developed at an accelerating pace. There has also been a shift in medicine from looking at large cohorts to looking at single individuals. In personalized or individualized medicine, it is all about how the individual is feeling with a specific treatment. We ask questions like “how can we optimize the care for this patient specifically?” While all philosophies in medicine are aimed at healing and helping, this is a different, more individualized way of doing that.

This interview was prompted by Sylvia Stockler’s research article “Developments in evidence creation for treatments of inborn errors of metabolism.” If you would like to learn more, please visit:

ACD Call to action:

As a caregiver or family member of someone with CCDS, we want to know what outcomes of CCDS from potential new treatments are the most important to you.

Take the Patient Meaningful Outcome Survey today at, and share your voice with the CCDS research community.

Our voices will lead the way.

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