Genomic and Electrophysiologic Factors Contributes to Clinical Endophenotypes in Autism and Epilepsy Populations

Background:  Autism spectrum disorders (ASD) are known to have complex inheritance patterns such as copy number variants (CNVs), single gene disorders, and rare mutations of common synaptic genes. Alteration in interneuron enriched genes may explain why perturbations of GABAergic circuitry have been implicated in common neurodevelopmental disorders such as autism (ASD), intellectual disability, and epilepsy. Defects in GABAergic migration, cell numbers, and circuit formation are found in animal models of autism and epilepsy. 

Objectives:  Our central hypothesis is that temporal and spatial specific expression of GABAergic signaling pathways contributes to the influence of sleep disruption on epileptiform discharges, seizure expression, and expression of clinical endophenotypes in autism populations.

Methods:  A unique database of autism epilepsy subjects (223), autism alone subjects (221), and epilepsy alone (242) was compiled by recording data from the medical records of 686 pediatric patients from Vanderbilt University and the University of Louisville. Comparisons were made between ASD alone, epilepsy alone, and ASD + epilepsy groups.  

Results:  Epilepsy alone (11.8 yrs), and autism-epilepsy subjects (11.5 yrs) were significantly older than ASD alone subjects (9.9 yrs, p<0.0001 ANOVA) with a male predominance in ASD groups (4-5: 1 M:F ratio in ASD groups vs 1:1 ratio in epilepsy alone group), p<0.0001). Even though there was a slightly significant difference in age of seizure onset (Epilepsy only 57 months vs ASD-Epilepsy, 62 months, p<0.05) and less % REM sleep (11% vs 16 to 18% for ASD groups, p<0.04), there were no difference in resistance to anti-seizure medications. Cognitive impairment plays a more significant role in autism epilepsy subjects (IQ=64) more so than the ASD alone (74), or epilepsy alone subjects (78, p<0.006). We did note that those with ASD + Epilepsy had a higher rate of detectable CNVs on clinical microarray testing (41%) than ASD alone (30%, p<0.08). In general, time at autism diagnosis was similar among the two ASD groups. Epilepsy subjects were significantly older when regression occurred (50 months, p<0.007) than those with ASD. Parent of children with ASD-Epilepsy reported more self injury and worse language use (P<0.008) on the Parental Concern Questionnaire than parents with ASD alone. Finally, consistent with parental reports of age at walking or talking, Vineland Adaptive Behavioral Adaptive Scales measures of Adaptive Composite as well as subscores (ADLs, Social, Communication, Motor) were significantly higher in ASD alone subjects (p=0.04 to 0.001) than ASD+ epilepsy subjects. However there were no differences among the two ASD groups on the Childhood Behavioral Checklist.

Conclusions:  Taken together, these data suggest that distinct subgroups within the autism and epilepsy populations have associated genomic variants which may impinge strongly on function of unique neural circuits and expression of clinical endophenotypes.