Abstracts

Rationale:
Infantile spasms (IS) or West Syndrome are a form of early life epilepsy (ELE) associated with seizures, developmental consequences and early mortality. IS has been associated with autism spectrum disorder (ASD), especially in children with tuberous sclerosis (TSC).The relationship between IS and ASD and the underlying molecular, pathological and clinical basis remain unclear, creating a care gap for children with IS.
Method:
We are performing biomarker-driven blood-based RNA-Sequencing and tandem LC-MSMS proteomics between genetically-confirmed IS+ASD and IS-ASD children of < 1 yr and < 3 yr cohorts to identify differential gene and protein expression and plasma cytokine profile to identify molecular and immune signatures. We are doing correlation analysis between genomic, transcriptomic, proteomic, and cytokine data with clinical features for significant biomarker identification specific to IS with the goal of identifying disease mechanisms in relation to ASD.
Results:
In our previous research, we found an overlap in molecular pathways affected by IS and that play a role in development of ASD. In a first comparative study of infants with (N=49) and without spasms over the course of 1yr follow-up (N=43) with definitive molecular diagnosis, we performed comparative gene ontology and pathway analysis on genes harboring pathogenic variants. Age of onset (AoO) of IS had a striking peak near 6 months whereas other seizures AoOs were more broader and heterogeneous suggesting tight relation with neurodevelopment. Gene-pathway analyses on 60 genes revealed that compared to other seizures, IS has a much broader impact on neurodevelopmental and immune signatures such as those associated with cytokines, chemokines, CD4+ T helper cells, PBMCs, macrophages, microRNAs such as miR200A and miR150 involved in cell growth, proliferation, TSC, and immune development. Of note, children with TSC2 pathogenic variants, but not TSC1 developed spasms while as expected most with Trisomy 21, CDKL5 developed spasms. Our analyses reveal a quintessential neurodevelopmental component of spasms with distinct peak of AoO, dysregulation of large numbers of developmental pathways that in turn, associated with higher chances of developmental delay. Moreover, dysregulated adaptive immunity and cytokine profiles are documented in ASD. These findings led to our hypothesis that there are molecular immune signatures associated with IS which predispose them to having ASD.
Conclusion:
This study can advance the understanding of the unique molecular underpinnings of infantile spasms and ASD that facilitate patient stratification for future therapeutic trials leading to better outcomes.
Funding:
:Pending