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Journal article
Why West? Comparisons of clinical, genetic and molecular features of infants with and without spasms
PloS one, v 13(3), pp e0193599-e0193599
08 Mar 2018
PMID: 29518120
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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.
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- Title
- Why West? Comparisons of clinical, genetic and molecular features of infants with and without spasms
- Creators
- Anne T. Berg - Children's Memorial HospitalSamya Chakravorty - Emory UniversitySookyong Koh - Emory UniversityZachary M. Grinspan - Cornell UniversityRenee A. Shellhaas - University of Michigan–Ann ArborRussell P. Saneto - University of WashingtonElaine C. Wirrell - Mayo Clinic Rochester, MNJason Coryell - Oregon Health & Science UniversityCatherine J. Chu - Harvard University ,John R. Mytinger - Nationwide Children's HospitalWilliam D. Gaillard - George Washington UniversityIgnacio Valencia - Drexel UniversityKelly G. Kriupp - Univ Colorado, Sch Med, Dept Pediat & Neurol, Anschutz Med Campus, Aurora, CO USATobias Loddenkemper - Harvard University ,Joseph E. Sullivan - University of California, San FranciscoAnnapurna Poduri - Harvard University ,John J. Millichap - Children's Memorial HospitalCynthia Keator - Jane and John Justin Neurosciences CenterCourtney Wusthoff - Stanford UniversityNicole Ryan - University of PennsylvaniaWilliam B. Dobyns - University of WashingtonMadhuri Hegde - Emory University
- Publication Details
- PloS one, v 13(3), pp e0193599-e0193599
- Publisher
- Public Library Science
- Number of pages
- 18
- Grant note
- K23NS092923 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) Pediatric Epilepsy Research Foundation, Dallas, TX
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pediatrics
- Web of Science ID
- WOS:000426902900027
- Scopus ID
- 2-s2.0-85043455232
- Other Identifier
- 991019168888504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Clinical Neurology