Abstracts

Rationale: Infantile spasms (IS) are the defining seizure type of West syndrome (WS), a form of early life epilepsy (ELE) associated with refractory seizures, developmental consequences and early mortality. Little is known about genes and molecular pathways that lead some infants to develop WS/IS while others do not. This is the first comparative study to examine molecular differences in infants with and without spasms. Methods: The ELE Study recruited 680 children with newly diagnosed epilepsy with onset < 3yr through 17 US-based epilepsy programs. 327/680 (48%) had ≥1 clinical genetic investigations, including karyotyping, chromosomal microarrays, epilepsy and mitochondrial gene-panel, exome, and other targeted tests. Of these, pathogenic variants were identified in 142 (44%) with epilepsy gene-panel testing giving highest diagnostic yield. We performed gene enrichment and molecular pathway analysis (p < 0.01; FDR < 0.05) on genes harboring pathogenic variants and epilepsy-associated genes affected by copy number variants (CNVs). We compared enrichment in pathways between spasms and non-spasms groups. Results: 60 pathogenic variant harboring genes with known or suspected epilepsy involvement were identified in 50 children with and 54 children without spasms. Onlyl 7 genes overlapped between the two groups. Gene-pathway analyses reveal a much broader spectrum of "biological pathways" affected in spasms compared to non-spasms group (fig1). For spasms, central nervous system (CNS) development, cell cycle regulation, cellular growth, mitochondrial metabolism, and broad immunological processes are more affected compared to non-spasm epilepsies. Interestingly, pathways of Alzheimer's and psychiatric disorders are uniquely enriched in spasms. By contrast, in non-spasm group maintenance and motor activity pathways (neuromuscular and motor neuronal processes, ion transport, and immunological responses by microglial cells) appear preferentially affected. There was a clear distinction of cellular component localization of pathogenic genes in both groups (fig2). In spasms, neuronal cellular organelles (Golgi, ER, mitochondria, lysosome, nucleus, centromere/kinetochore, cytoskeleton, dendrites) were uniquely enriched. By contrast, in non-spasm group, axonal areas such as synapse, node of Ranvier, and plasma membrane were preferentially enriched. We also found a greater enrichment of microRNA regulated gene targets in the spasms group. Of note, no children with SCN1A or PRRT2 pathogenic variants developed spasms while most with Trisomy 21, CDKL5, TSC2, but not TSC1 developed spasms. Conclusions: Our analyses reveal the neurodevelopmental nature of spasms which are associated with multiple factors causing dysregulation of large numbers of developmental pathways. The data suggest genetic and cellular component dichotomies between IS and other ELEs. Such findings can advance the understanding of the unique molecular underpinning of spasms and may play a role in patient stratification for future therapeutic trials. Such goals could be facilitated by the use of whole genome sequencing. Funding: The Pediatric Epilepsy Research Foundation, Dallas, TX (PI, Dr. Berg).