Beyond Seizure Management in a Developmental Epileptic Encephalopathy: Expanding the SLC6A1 Neurodevelopmental Disorder Phenotype.

Background and Objectives: SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD) is emerging as a leading genetic cause of epilepsy, autism spectrum disorder (ASD), and NDD caused by monoallelic loss of function variants in SLC6A1 (solute carrier family 6 member 1) which encodes a gamma-aminobutyric acid (GABA) transporter (GAT1). Descriptions of SLC6A1-NDD have centered around epilepsy, but caregivers report other features that drive key aspects of the disease burden. This retrospective chart review and prospective natural history study (NHS) aims to highlight the nonseizure clinical features of SLC6A1-NDD. Methods: Medical records of individuals with SLC6A1-NDD from University of Texas Southwestern (UTSW) and from the Children's Hospital of Philadelphia (CHOP) were reviewed. Participants had a confirmed or strongly suspected pathogenic variant in SLC6A1. Twenty of these individuals were also enrolled in an NHS at UTSW which included standardized scales and caregiver interviews. Results: Sixty-three individuals were included (40 from UTSW, 23 from CHOP) with 31 males. Developmental delay was present in 97%, developmental regression in 41%, and 58% of those had an atypical regression. Of the total cohort, 60% have ASD. Maladaptive behaviors were present in a majority with aggression occurring in 57% of those. Twenty individuals completed standardized scales as part of the NHS at UTSW. The developmental coordination disorder questionnaire (DCDQ) demonstrated that 90% met criteria for probable developmental coordination disorder. Sleep problems were reported in 56%, but when assessed with the sleep disturbance scale for children (SDSC), all NHS participants scored >39, indicating clinically significant sleep problems. Total SDSC score positively correlated with behavior problems. Discussion: Daily effects from SLC6A1-NDD cannot be described by epilepsy alone. Combining retrospective and prospective NHS data expands phenotypic and genotypic knowledge. We report the highest association with ASD and unusual developmental regression patterns. Maladaptive behaviors are frequent, commonly aggression. DCDQ and SDSC scores correlated with caregiver concerns but also found higher instances of movement and sleep problems, underrecognized by caregivers and providers. Often, odd movements defy categorization between stereotypies, tics, and epileptic movements. GABA homeostasis disruptions are integral to symptom formation but require better understanding.