DCM. This is my second blog post on SYNGAP1-related disorders within a month, which highlights how fast the area of clinical trial readiness is moving for one of the most common synapse disorders. Over the last few years, we have become more and more attuned to the fact that readying genetic epilepsies for clinical trials requires a systematic approach. The first step in this process is a disease concept model (DCM). In a recent publication in Pediatric Neurology, the authors comprehensively mapped the lived experience of SYNGAP1-related disorders. Here is what the authors found.
Figure 1. Symptoms in SYNGAP1-related disorders most frequently mentioned by caregivers assessed through interviews by Cunnane and collaborators. Difficulties with behaviors and communication are reported more frequently by families than seizures, highlighting the complexity of SYNGAP1-related disorders and providing a framework for outcomes measures to be tracked in natural history studies such as SYNGAP1 ProMMiS and future clinical trials (Figure modified from Cunnane et al., 2025).
Disease Concept Models. I must admit that I was initially very slow to understand what a disease concept model actually is and what it represents. At first, this sequence of words sounds harmless and even somewhat trivial. However, as I learned from our own experience in creating a DCM for STXBP1-related disorders, it is a very clearly defined concept. As with the Standard Model in physics or a Foundational Model for generative AI, it has a very specific meaning. In brief, a DCM is structured framework using qualitative methods including interviews, literature review, and focus groups to capture how a disease impacts patients and caregivers. It is a formal framework to map the lived experience of a condition holistically and in a conclusive, definitive way. For SYNGAP1 where a multisite natural history study (SYNGAP1 ProMMiS) has already been underway for the last two years, it provides additional reassurance for our selection of specific outcome measures.
Concept saturation. Qualitative research includes the framework of concept saturation. Information from interviews is transcribed, and the content is assigned to specific concepts. This activity is referred to as “coding” and is typically performed through specific software tools such as Atlas.ti or NVivo. With an increasing number of interviews, these concepts will become “saturated”, which means that existing concepts (such as “behavior” or “seizures” in SYNGAP1) will be addressed repeatedly, while no new concepts emerge during further interviews. Typically, the point of concept saturation is reached after 10-15 interviews.
Holistically. When I heard about concept saturation the first time, the value of DCMs became immediately clear to me: DCMs are a structured method to capture the entirety of a lived experience; they provide a global map that tells you: “Here is a full description of what the disease is about”. DCMs are not primarily meant to be earth-shattering and identify entirely new areas that were unknown to the rare disease community—in fact, given that the SYNGAP1 community is closely knit, we will likely have heard many of these issues from our SYNGAP1 families already. However, clinical care and even structured research studies typically do not have good mechanisms to describe all symptoms affecting the SYNGAP1 community systematically. In addition, symptoms outside a provider’s specialty often receive less attention during clinic visits and patient notes. This is where a DCM comes in: it is meant to be comprehensive, definite, and conclusive.
SYNGAP1. DCMs typically include a literature review and interviews with caregivers as the main components. For the DCM for SYNGAP1, Cunnane and collaborators went further, surveying caregivers and performing a comprehensive chart review of individuals with SYNGAP1-related disorders seen at their center. The authors interviewed 16 caregivers and 15 clinical experts, reviewed 19 publications, and analyzed survey responses from 90 caregivers. In brief, difficult behaviors, impaired communication, impaired gross motor skills, developmental differences, seizures, and sleeping difficulties were the most reported symptoms in the caregiver interviews. Through surveys, Cunnane and collaborators also addressed therapeutic targets in SYNGAP1-related disorders. Intellectual disability, communication, emotional regulation, and seizures were identified as the core components of SYNGAP1-related disorders that could be addressed in future trials. This aspect of the study by Cunnane and collaborators is particularly noteworthy, as it adds an additional aspect to the DCM, distinguishing the core components of SYNGAP1-related disorders from specific aspects that may represent treatment targets. For example, the high pain tolerance and restrictive and repetitive behaviors in SYNGAP1 are core components of the condition but are not consider high priority therapeutic targets according to caregivers and clinicians.
Outcome measures. Cunnane and collaborators provide a list of established outcome measures by which the core components of SYNGAP1-related disorders can be assessed. This aspect of their publication provides a nice transition from their DCM to SYNGAP1 ProMMis, which is already using measures such as the Bayley Scales of Infant and Toddler Development, the Observed-Reported Communication Ability (ORCA), and seizure reconstructions through the PELHS seizure frequency scale. In brief, Cunnane and collaborators provide additional support that ongoing clinical trial readiness studies are founded in the lived experience of caregivers of individuals with SYNGAP1-related disorders and are not missing major aspects of the condition.
What you need to know. In their publication in Pediatric Neurology, Cunnane and collaborators present a disease concept model for SYNGAP1-related disorders, providing a comprehensive view of the lived experience of caregivers. Caregivers and providers identified seizures, intellectual disability, communication, and emotional regulation as the most important targets for future clinical trials, providing an important sanity check for the outcome measures that are in current use in the SYNGAP1 ProMMiS Natural History Study.
