Why West? Comparisons of clinical, genetic and molecular features of infants with and without spasms

• Type of Material: Article
• Authors: Anne T. Berg, Ann & Robert H Lurie Children's Hospital Chicago; Samya Chakravorty, Emory University; Sookyong Koh, Emory University; Zachary M. Grinspan, Weill Cornell Medicine; Renee A. Shellhaas, University of Michigan; Russell P. Saneto, Seattle Children's Hospital; Elaine C. Wirrell, Mayo Clinic; Jason Coryell Coryell, Oregon Health and Science University; Catherine J. Chu, Massachusetts General Hospital; John R. Mytinger, Ohio State University; William D. Gaillard, George Washington University; Ignacio Valencia, Drexel University; Kelly G. Kriupp, University of Colorado; Tobias Loddenkemper, Harvard Medical School; Joseph E. Sullivan, University of California San Francisco; Annapurna Poduri, Harvard Medical School; John J. Millichap, Ann & Robert H Lurie Children's Hospital of Chicago; Cynthia Keator, Jane & John Justin Neuroscience Center; Courtney Wusthoff, Stanford University; Nicole Ryan, Children's Hospital of Philadelphia; William B. Dobyns, Seattle Children's Hospital; Madhuri Hegde, Emory University
• Language: English
• Date: 2018-03-08
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2018 Berg et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0193599
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 13
• Issue: 3
• Start Page: e0193599
• End Page: e0193599
• Grant/Funding Information: The study was funded by a grant from the Pediatric Epilepsy Research Foundation, Dallas, TX. (ATB) http://pediatricepilepsyresearchfoundation.org/.
• Keywords: CHILDREN; LONG-TERM PROGNOSIS; BRAIN-DEVELOPMENT; Science & Technology; Science & Technology - Other Topics; DOWN-SYNDROME; EPILEPSY; CELL-PROLIFERATION; CHEMOKINE RECEPTORS; MENTAL-RETARDATION; TUBEROUS SCLEROSIS COMPLEX; SEIZURES; Multidisciplinary Sciences
• Research Categories: Biology, Genetics; Health Sciences, Medicine and Surgery

Abstract

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Infantile spasms are the defining seizures of West syndrome, a severe form of early life epilepsy with poorly-understood pathophysiology. We present a novel comparative analysis of infants with spasms versus other seizure-types and identify clinical, etiological, and molecular-genetic factors preferentially predisposing to spasms. We compared ages, clinical etiologies, and associated-genes between spasms and non-spasms groups in a multicenter cohort of 509 infants ( < 12months) with newly-diagnosed epilepsy. Gene ontology and pathway enrichment analysis of clinical laboratory-confirmed pathogenic variant-harboring genes was performed. Pathways, functions, and cellular compartments between spasms and non-spasms groups were compared. Spasms onset age was similar in infants initially presenting with spasms (6.1 months) versus developing spasms as a later seizure type (6.9 months) but lower in the non-spasms group (4.7 months, p < 0.0001). This pattern held across most etiological categories. Gestational age negatively correlated with spasms onset-age (r = -0.29, p < 0.0001) but not with non-spasm seizure age. Spasms were significantly preferentially associated with broad developmental and regulatory pathways, whereas motor functions and pathways including cellular response to stimuli, cell motility and ion transport were preferentially enriched in non-spasms. Neuronal cell-body organelles preferentially associated with spasms, while, axonal, dendritic, and synaptic regions preferentially associated with other seizures. Spasms are a clinically and biologically distinct infantile seizure type. Comparative clinical-epidemiological analyses identify the middle of the first year as the time of peak expression regardless of etiology. The inverse association with gestational age suggests the preterm brain must reach a certain post-conceptional, not just chronological, neurodevelopmental stage before spasms manifest. Clear differences exist between the biological pathways leading to spasms versus other seizure types and suggest that spasms result from dysregulation of multiple developmental pathways and involve different cellular components than other seizure types. This deeper level of understanding May guide investigations into pathways most critical to target in future precision medicine efforts.