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PLoS One. 2018 Mar 8;13(3):e0193599. doi: 10.1371/journal.pone.0193599. eCollection 2018.

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

Author information

1
Epilepsy Center, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States of America.
2
Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States of America.
3
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States of America.
4
Department of Pediatrics, Children's Healthcare of Atlanta, Emory University, Atlanta, GA, United States of America.
5
Department of Healthcare Policy & Research, Weill Cornell Medicine, New York, NY, United States of America.
6
Department Pediatrics, Weill Cornell Medicine, New York, NY, United States of America.
7
New York Presbyterian Hospital, New York, NY, United States of America.
8
Department of Pediatrics, University of Michigan, Ann Arbor, MI, United States of America.
9
Division of Pediatric Neurology, Seattle Children's Hospital, Seattle, WA, United States of America.
10
Department of Neurology, University of Washington, Seattle, WA, United States of America.
11
Department of Neurology, Mayo Clinic, Rochester, MN, United States of America.
12
Departments of Pediatrics & Neurology, Oregon Health & Sciences University, Portland, OR, United States of America.
13
Department of Neurology, Massachusetts General Hospital, Boston, MA, United States of America.
14
Department of Pediatrics, the Ohio State University, Nationwide Children's Hospital, Columbus, OH, United States of America.
15
Department of Neurology, Children's National Health System, George Washington University School of Medicine, Washington, D.C., United States of America.
16
Section of Neurology, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA, United States of America.
17
Department of Pediatrics and Neurology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America.
18
Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States of America.
19
Department of Neurology, University of California San Francisco, San Francisco, CA, United States of America.
20
Cook Children's Health Care System, Jane and John Justin Neurosciences Center, Fort Worth, TX, United States of America.
21
Division of Child Neurology, Stanford University, Palo Alto, CA, United States of America.
22
Departments of Neurology and Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.
23
The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States of America.
24
Center for Integrative Brain Research, University of Washington, Seattle, WA, United States of America.
25
Seattle Children's Research Institute, University of Washington, Seattle, WA, United States of America.
26
Pediatrics University of Washington, Seattle, WA, United States of America.

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.

PMID:
29518120
PMCID:
PMC5843222
DOI:
10.1371/journal.pone.0193599
[Indexed for MEDLINE]
Free PMC Article

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