Table Of ContentDavid D. Eisenstat · Dan Goldowitz ·
Tim F. Oberlander · Jerome Y. Yager Editors
Neurodevelopmental
Pediatrics
Genetic and Environmental Influences
123
Neurodevelopmental Pediatrics
David D. Eisenstat • Dan Goldowitz
Tim F. Oberlander • Jerome Y. Yager
Editors
Neurodevelopmental
Pediatrics
Genetic and Environmental Influences
Editors
David D. Eisenstat Dan Goldowitz
Department of Paediatrics Department of Medical Genetics
University of Melbourne University of British Columbia
Parkville, VIC, Australia Vancouver, BC, Canada
Tim F. Oberlander Jerome Y. Yager
Department of Pediatrics and School Department of Pediatrics
of Population and Public Health University of Alberta
University of British Columbia Edmonton, AB, Canada
Vancouver, BC, Canada
ISBN 978-3-031-20791-4 ISBN 978-3-031-20792-1 (eBook)
https://doi.org/10.1007/978-3-031-20792-1
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Preface
Long before COVID-19, NeuroDevNet, a Canadian multidisciplinary network of clinicians,
scientists, and trainees, recognized an unmet need in the neurodevelopmental field, where
common clinical problems in Pediatric Neurology and Developmental Pediatrics needed to
be thematically linked with current concepts and translational research advances that applied
evidence-based interventions harnessing advances in Developmental Neurosciences,
Medical Genetics, Allied Health, and related disciplines. Addressing this need would con-
tribute to improving the lives of children and families living with brain-based developmental
disorders.
In the pages that follow, we focus on advancing our understanding of the impact of genetics,
environment, or both using three specific pediatric developmental disorders as exemplars of
key neurodevelopmental conditions. Using autism/autism spectrum disorders (ASD; predomi-
nantly an underlying genetic predisposition), fetal alcohol spectrum disorder (FASD; predomi-
nantly an underlying environmental etiology), and cerebral palsy (CP; with combined genetic
and environmental contributions), we discuss neurodevelopment spanning from molecular,
behavioral, and contextual/family considerations.
The first section of the textbook provides a comprehensive and up-to-date overview of
the basic science of development of the brain, including sections on stem cells, epigenetics,
and the influence of the perinatal environment. This is followed by sections 2–4 where the
broader scope of the three selected developmental disabilities is discussed, including the
impact of genetic, epigenetic, and environmental contexts. Against the backdrop of cate-
gorical approaches to neurodevelopmental disabilities, a discussion of non-categorical
dimensional approaches to assess and understand child and family health and well-being
is also presented. Then chapters follow that discuss key comorbidities common to all three
disorders, such as disturbed sleep, seizures, behavioral disorders, and pain. This is fol-
lowed by chapters covering the impact of ASD, FAS, and CP on family dynamics, their
economic impact, and service delivery to the community. Finally, important resources are
provided on harnessing data as well as knowledge translation and dissemination to the
community and other stakeholders. Many chapters offer a discussion of controversies and
research directions as well as clinical perspectives or vignettes that provide a comprehen-
sive approach to neurodevelopmental disabilities that will be of great interest to trainees,
clinicians, and researchers alike. Our target readership are individuals with interests in
the developing brain and how perturbations of that development can lead to neurodevel-
opmental disabilities. The aim of the text is to provide clinical and basic science trainees
(residents, clinical fellows, graduate students, postdoctoral fellows) with a strong ground-
ing in understanding disorders of the developing brain with a view to these trainees
becoming the next generation of child neurologists, developmental pediatricians, and
developmental neuroscientists.
As co-editors, we are indebted to our contributing authors who have devoted significant
time and effort to ensure that this textbook meets the educational and biomedical needs of all
v
vi Preface
stakeholders in the neurodevelopmental community. Finally, we extend our sincere apprecia-
tion to our publishers from Springer Nature, especially Pinky Sathishkumar, who ensured that
this new textbook became a reality.
Parkville, VIC, Australia David D. Eisenstat
Vancouver, BC, Canada Dan Goldowitz
Vancouver, BC, Canada Tim F. Oberlander
Edmonton, AB, Canada Jerome Y. Yager
July 13, 2022
Acknowledgment
The Editors would like to thank the National Centres of Excellence (Canada) for supporting
NeuroDevNet and the Kids Brain Health Network (KBHN). The establishment of these
Networks as a foundation for research platforms in neurodevelopmental disorders in children
served as the inspiration to establish and pursue publication of this textbook as a global com-
munity investigating brain-based disorders common to the growing infant and child.
We further wish to acknowledge a host of funding agencies which have supported research
specifically related to work done by the Editors inclusive of the Canadian Institutes of Health
Research (CIHR), the Canadian Foundation for Innovation, the Heart and Stroke Foundation
of Canada, the Natural Sciences and Engineering Council of Canada (NSERC), the Women’s
and Children’s Health Research Institute at the University of Alberta (WCHRI), the BC
Children’s Hospital Research Institute, the Kids with Cancer Society (Edmonton), and the
Government of Canada’s Canada Research Chairs program.
The Editors would also like to thank the clinical and research trainees in Pediatrics, Pediatric
Neurology, Developmental Pediatrics, Medical Genetics and Developmental Neuroscience at
the University of British Columbia and University of Alberta, as well as both NeuroDevNet
and the KBHN, for providing the inspiration for the textbook.
The Editors wish to express their sincere gratitude and appreciation to all of the chapter
authors and co-authors of this textbook. The chapters provide an international perspective on
the normal and abnormal developing child’s brain. Moreover, the editors have appreciated the
patience of all concerned during this trying time of the COVID-19 pandemic with all of the
challenges it has brought.
Finally, the Editors are grateful to their families for their generous encouragement and sup-
port throughout the journey, from the textbook’s inception to its launch.
vii
Contents
Part I Overview of CNS Development and Disorders
1 Overview of CNS Organization and Development . . . . . . . . . . . . . . . . . . . . . . . . . 3
Richard E. Brown
2 Neural Induction and Regionalization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Jeffrey T. Wigle and David D. Eisenstat
3 Neural Stem Cells, Differentiation, and Migration . . . . . . . . . . . . . . . . . . . . . . . . . 39
Jessica M. Livingston, Emily A. B. Gilbert, Donna Gao, and Cindi M.
Morshead
4 Neurotrophins and Cell Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Arman Shekari, Crystal Mahadeo, Nisha Sanwalka, and Margaret Fahnestock
5 Synaptogenesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Margaret H. Hastings, James Gilbert, Yuda Huo, and Heng-Ye Man
6 Axonal Guidance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Mikaela Nevin, Janine Gallego, and David D. Eisenstat
7 Myelination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .107
Janine Gallego, Mikaela Nevin, and David D. Eisenstat
8 Epigenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .123
Helena Biasibetti-Brendler and Michael Steffen Kobor
9 The Impact of an Adverse Intrauterine Environment on
Neurodevelopment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .147
Sindhu Ramachandra, Michelle Low, Nethra Madurai, Maide Ozen,
Yuma Kitase, Shenandoah Robinson, and Lauren L. Jantzie
10 Stress as a Determinant of Neurodevelopmental Outcomes . . . . . . . . . . . . . . . . . .165
Bona Kim and Stephen G. Matthews
11 Sex Differences in Neurodevelopment and Its Disorders . . . . . . . . . . . . . . . . . . . .179
Richard E. Brown
Part II A utism Spectrum Disorders
12 The History of Autism Spectrum Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .215
Alexandra Jackman and Lonnie Zwaigenbaum
13 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .227
Mayada Elsabbagh
ix
x Contents
14 An Approach to the Diagnosis of Autism Spectrum . . . . . . . . . . . . . . . . . . . . . . . . .243
Cecilia Lee and Melanie Penner
15 Autism Spectrum Disorder: Cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .253
Elizabeth Kelley and Alison Dodwell
16 The Neuroradiology of Autism: Framing Neuroimaging Investigations
of the Autistic Brain Based on the US NIMH Research Domain Criteria . . . . . . .269
Hsiang-Yuan Lin and Meng-Chuan Lai
17 Neuropathology of Autism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .283
Yarden Kezerle
18 Genetics and Epigenetics of ASD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .293
Bahareh A. Mojarad, Farah Qaiser, and Ryan K. C. Yuen
19 Preclinical Models of Autism Spectrum Disorder . . . . . . . . . . . . . . . . . . . . . . . . . .309
Stephania Assimopoulos, Antoine Beauchamp, and Jason P. Lerch
20 Biomedical Interventions for Autism Spectrum Disorder . . . . . . . . . . . . . . . . . . . .327
Janys Joy Lim and Evdokia Anagnostou
21 Interventions in ASD: Psychosocial Interventions and Supports for ASD . . . . . .337
Jessica A. Brian, Isabel M. Smith, and Katherine Stover
Part III Fetal Alcohol Spectrum Disorder
22 Clinical Perspectives on the Diagnostic Assessment of Individuals
with FASD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .353
Ana C. Hanlon-Dearman and Sally Longstaffe
23 Epidemiology of Alcohol Consumption among Pregnant and
Childbearing Age Women and Fetal Alcohol Spectrum Disorder . . . . . . . . . . . . .371
Svetlana Popova, Jürgen Rehm, and Kevin Shield
24 Fetal Alcohol Spectrum Disorder: Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .379
Jocelynn L. Cook and Courtney R. Green
25 Magnetic Resonance Imaging in Fetal Alcohol Spectrum Disorder (FASD) . . . . .397
Catherine Lebel and Ashley Ware
26 Neuropathological Changes in Humans with History of Prenatal
Alcohol Exposure or Diagnosis of Fetal Alcohol Spectrum Disorder . . . . . . . . . .409
Marc R. Del Bigio
27 Genetics and Epigenetics of FASD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .425
Jessica A. Baker, Shuliang Yu, Matthew T. Scott, and Kristin M. Hamre
28 Genetic, Epigenetic, and Environmental Influences on Fetal Alcohol
Spectrum Disorder: Implications for Diagnosis, Research and Clinical Practice 441
Alexandre A. Lussier, Berardino Petrelli, Geoffrey G. Hicks, and Joanne
Weinberg
29 Fetal Alcohol Spectrum Disorder: Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . .457
Jacqueline Pei, Aamena Kapasi, and Carmen Rasmussen
Contents xi
Part IV Cerebral Palsy
30 Cerebral Palsy: Clinical Vignettes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .469
Michael Shevell
31 Cerebral Palsy: Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .479
Shona Goldsmith, Sarah McIntyre, Eve Blair, Hayley Smithers-Sheedy, Nadia
Badawi, and Michele Hansen
32 Diagnosis of Cerebral Palsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .497
Young-Min Kim and Stephen Ashwal
33 Neuroradiology of Cerebral Palsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .515
Fatema Al Amrani, Christine Saint-Martin, and Pia Wintermark
34 Neuropathology of Cerebral Palsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .533
Harvey B. Sarnat
35 Genetics and Genomics of Cerebral Palsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .547
Jan Friedman and Clara van Karnebeek
36 Pre-Clinical Models of Cerebral Palsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .569
Zeenat Ladak and Jerome Y. Yager
37 Therapeutic Approaches for the Treatment of Cerebral Palsy
and Developmental Disability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .579
Michael G. Fehlings, Stephanie R. Beldick, Janette Mailo, Oriana Shaw, Sarah
Almas, and Jerome Y. Yager
Part V Co-Morbidities in Neurodevelopmental Disorders
38 Sleep Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .613
Gabrielle Rigney, Pratima Gulati, Penny Corkum, and Shelly K. Weiss
39 Optimizing Therapy of Seizures in Children and Adolescents
with Developmental Disabilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .631
Anthony Fine, Elaine Wirrell, and Katherine Nickels
40 Behavioral and Mental Health Disorders (Including Attentional Disorders) . . . .655
I. Leslie Rubin, Claire D. Coles, and Jarrett Barnhill
41 Role of Gender and Neurodevelopmental Disabilities . . . . . . . . . . . . . . . . . . . . . . .675
Donald E. Greydanus, Dilip R. Patel, and Joav Merrick
42 A Non-Categorical Approach to Childhood Neurodisability: Concepts, Evidence,
and Implications for Clinical Practice, Organization of Services, Teaching, and
Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .685
Anton R. Miller, Emily Gardiner, and Peter L. Rosenbaum
43 Pain and Symptom Management in Neurodevelopmental Disorders: Sensory and
Nociceptive Function/Pain and Symptom Management . . . . . . . . . . . . . . . . . . . . .697
Chantel Burkitt, Lara Genik, Alyssa Merbler, Hal Siden, Tim F. Oberlander,
and Frank Symons
44 Pharmacology, Psychopharmacology, and Adverse Drug Reactions . . . . . . . . . . .713
Jarrett Barnhill, Roberto A. Blanco, Kateland Napier, and Takahiro Soda
