Authors :
Presenting Author: Marie Varnet, MD – University of Colorado
Sanjana Kalvakuntla, MD – University of Texas Southwestern Medical Center
Corinne Hunnicutt, BA – COMBINEDBrain
Sandra McEntee, BS – SLC6A1 Connect
Gary Heiman, PhD – Rutgers University
Dallas Armstrong, MD – UT Southwestern
Sarah Poliquin, PhD – COMBINEDBrain
Rationale:
SLC6A1-NDD is a rising cause of epilepsy and autism. SLC6A1 haploinsufficiency disrupts GABA homeostasis causing neurobehavioral changes presenting with developmental delay and later with seizures. Disease concept models (DCM) are frameworks built by engaging the community to understand the drivers of symptom burden. We present major impact domains from the SLC6A1-NDD DCM.
Methods:
Semi-structured interviews were conducted with caregivers of individuals with SLC6A1-NDD. Participants were recruited through the UTSW natural history study and the patient advocacy group, SLC6A1 Connect. Hour-long interviews were recorded, transcripts anonymized then independently coded using Dedoose software by paired teams. Codes were normalized by co-code application per transcript to account for unconscious bias in interview and coding styles.
Results:
A total of 17 caregivers were interviewed. Neurologic and behavior domains were identified as having the biggest impacts on caregivers, leading to increased caregiver effort, emotional impacts, and socialization changes (each co-coded together 76% of the time). Disrupted behavior and sleep were especially noted to impact caregiver health (41% and 47% co-codes respectively). Within those major domains, maladaptive behavior, unpredictable behavior, aggression, and autism had the largest emotional impacts on caregivers while disinhibition and abnormal social behavior had the largest impacts socially (including impacts on siblings, family social isolation, and stigma). Seizures and motor disruptions (including motor skills and movement disorders) had the largest impacts on caregiver effort required. Caregivers indicated that behavior made the biggest impacts on the individuals with SLC6A1-NDD (88% co-codes), especially regarding education and socialization. Closely related symptom domains were cognition, communication, and emotional; all of which also had high caregiver and individual impacts. Over time, impacts across most domains peak between ages 5 to 11 years old. Impacts from behavior remain higher than nearly every other domain across age groups (peaking at 77%), matching impacts from emotional symptoms in the above 18 years old group (24% co-codes). Impacts from seizures are highest before the age of 11 (ranging from 59 to 77% co-codes), after which impacts drop off significantly (12 to 18%).
Conclusions:
Developing a DCM brings the caregivers and individuals most closely affected by a disorder into the research process. By doing this, we establish goals for natural history studies and clinical trials that most align with the lived experience. As targeted therapies are developed, this DCM will support the importance of behavior and emotional intervention across all ages. While seizures and other neurologic symptoms have great impacts, they cannot overshadow what caregivers have expressed to be the biggest barriers to education, socialization, sibling relationships, and caregiver health.
Funding:
Funding was provided in part by SLC6A1 Connect.