Peripheral Lymphocytic Extracellular Signal Related Kinase Activation in Young Children with Autism Spectrum Disorder

Background: Given the phenotypic variability within autism spectrum disorder (ASD), peripheral blood biomarker development offers the potential to objectively predict and measure treatment response. Additionally, peripheral biomarkers may aid early diagnosis and potentially predict disease severity. Biomarker development in ASD has been met with limited success to date. Recently, biomarker development has focused on looking at central points of cellular signaling and activity such as the extracellular signal-related kinase (ERK) signaling cascade. The ERK cascade plays critical roles in brain development, learning, and memory and has been linked with many neurogenetic disorders associated with ASD, including FXS, TS and neurofibromatosis.  

Objectives: The purpose of this study was to examine ERK activation in peripheral lymphocytes in young children with ASD, aged 3 to 5 years old compared to age- and gender-matched neurotypical controls.   

Methods: ASD diagnosis was based upon clinical interview with the Autism Diagnostic Observation Schedule completed by a research reliable examiner along with a score greater than or equal to 15 on the Social Communication Questionnaire (SCQ). Additional ASD subject characterization was done using the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS) and Vineland Adaptive Behavior Scales.  Participants with ASD had stable psychotropic drug dosing. Diagnosis of schizophrenia, another psychotic disorder, bipolar disorder, or alcohol or other substance abuse based on DSM-V criteria was exclusionary. Participants completed an extracellular signal-regulated kinase (ERK) activation assay administered at baseline and 8-12 weeks later to provide test-retest data. Neurotypical control subjects participated in baseline blood testing only to limit subject burden. ERK lymphocyte activation assays were completed by flow cytometry blind to participant diagnosis. Comparisons include baseline ERK activation (phosphorylation) and time to half maximum ERK phosphorylation following phorbol myristate acetate stimulation.   

Results: There were 15 children in each group (4 female). Groups were matched for age with a mean ages of 4.5 and 4.2 in the ASD and control groups respectively (p=0.26). Groups were not matched on IQ with the children with ASD having a significantly lower IQ. Children with ASD had a significantly higher baseline ERK activation as compared to the control group (p=0.037).  The time to half-maximum phosphorylation did not differ between groups (ASD M=5.67 minutes s.d.=0.84, Control M=5.87 s.d.=0.84 minutes, p=0.662). 

Conclusions: ERK is a promising potential biomarker for ASD in young children. Further work is needed to fully understand how it may serve to aid in monitoring of treatment response or early identification.