Clinical Neuroembryology

Hans J. ten DonkelaarMartin Lammens Akira Hori

Development and Developmental Disorders of the Human Central Nervous System

Second Edition

Clinical Neuroembryology

Hans J. ten Donkelaar • Martin Lammens Akira Hori

Clinical Neuroembryology

Development and Developmental Disorders of the Human Central Nervous System

Second Edition

In co-operation with:

Eleonora AronicaMireille BekkerJohannes R.M. CruysbergKyoko ItohKarin Kamphuis-van UlzenIrene M.J. MathijssenRonald PenningsWilly O. RenierKohei Shiota

Hans van Bokhoven Ton van der VlietPatrick van der VoornJohn M.G. van VugtChristl Vermeij-KeersPieter WesselingMichèl WillemsenShigehito Yamada

Hans J. ten Donkelaar , M.D., Ph.D. 935 Department of Neurology Radboud University Nijmegen Medical Centre Nijmegen , The Netherlands

Martin Lammens , M.D., Ph.D. Department of Pathology University Hospital Antwerpen Edegem , Belgium

Akira Hori , M.D., Ph.D. Institute of Pathology Medizinische Hochschule Hannover Hannover , Germany

Research Institute for Longevity Medicine Fukushimura Hospital Toyohashi , Japan

ISBN 978-3-642-54686-0 ISBN 978-3-642-54687-7 (eBook) DOI 10.1007/978-3-642-54687-7 Springer Heidelberg New York Dordrecht London

Library of Congress Control Number: 2014940543

© Springer-Verlag Berlin Heidelberg 2006, 2014 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifi cally for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher's location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein.

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Apart from a general updating of the extensive literature on developmental neurobiology, neu-rogenetics, imaging and developmental neuropathology between 2005 and 2013, more empha-sis has been given to: (a) imaging of the embryonic brain (early prenatal diagnosis by ultrasound); (b) imaging of the fetal brain by MRI; (c) DTI studies on the development of major fi bre connections such as the pyramidal tract and the corpus callosum; and (d) the impact of newer genetic techniques such as whole exome/genome sequencing. Moreover, new clas-sifi cations of brain disorders have been implemented such as a new classifi cation of midbrain- hindbrain developmental disorders and entire new families of disorders such as ciliopathies and dystroglycanopathies. Throughout the book, several new Clinical Cases have been added.

Several colleagues kindly contributed as new co-authors their expertise to this second edi-tion, including Eleonora Aronica (Amsterdam), Mireille Bekker (Nijmegen), Kyoko Itoh (Kyoto), Karin Kamphuis-van Ulzen (Nijmegen), Irene Mathijssen (Rotterdam), Ronald Pennings and Hans van Bokhoven (Nijmegen), Patrick van der Voorn (Amsterdam) and Shigehito Yamada (Kyoto). They also contributed new Clinical Cases. For other new Clinical Cases, the help of Remke Dullemond (Rotterdam), Janet Eyre (Newcastle), Floris Groenendaal (Utrecht), Gregor Kasprian (Vienna), Hajime Miyata (Akita), Peter Nikkels (Utrecht), Tetsu Niwa (Yokohama), Andrea Poretti (Zurich), Ritsuko Pooh (Osaka), Goran Simić (Zagreb) and Marjolein Willemsen (Nijmegen) is gratefully acknowledged. New illustrations were also kindly provided by Marco Catani and Michel Thiebaut de Schotten (London), Cyrille Ferrier (Utrecht), Hao Huang (Dallas), Ole Kiehn (Stockholm), Grace Lai (New York), Anna Lavezzi (Milan) and Maria Thom (London). A long weekend with Luis Puelles in Murcia greatly helped the fi rst author to implement new fi ndings on the prosomeric model of the developing brain.

Hans J. ten Donkelaar , Nijmegen Martin Lammens , Edegem

Akira Hori , Toyohashi

Preface to the Second Edition

vii

Preface to the First Edition

The spectacular progress in developmental neurobiology, the tremendous advances in (neuro)genetics and the high resolution of the modern imaging techniques applicable to developmen-tal disorders of the human brain and spinal cord have created a growing interest in the devel-opmental history of the central nervous system (CNS). This new book provides a comprehensive overview of the development of the human CNS in the context of its many developmental disorders due to genetic, environmental and hypoxic/ischemic causes. The book contains three general, introductory chapters in which an overview of the development of the human brain and spinal cord, a summary of mechanisms of development as obtained in experimental studies in various invertebrates and vertebrates, and an overview of the causes of congenital malforma-tions with some notes on prenatal diagnosis, are presented. The developmental disorders of the human brain and spinal cord are presented in a regional, more or less segmental way, starting with neurulation and the neural tube defects, and ending with developmental disorders of the cerebral cortex. These chapters are abundantly illustrated with clinical case studies with imag-ing data and, when available, postmortem verifi cation of the developmental disorders involved. The book is intended for advanced medical students, and all those clinicians working with children and adults with developmental disorders of the CNS.

This book would not have been possible without the help of many colleagues in The Netherlands and from abroad. Their help is gratefully acknowledged. Most of the neuropatho-logical material comes from the extensive collections of Drs. Akira Hori and Martin Lammens. Many cases were kindly provided by Drs. Pieter Wesseling (Nijmegen), Gerard van Noort (Enschede), and Kohei Shiota (Kyoto). Photographical assistance was provided by Mrs. Roelie de Boer-van Huizen (Nijmegen), Mrs. Chigako Uwabe (Kyoto) and Richard Rieksen (Enschede). Material for the clinical case studies was provided by many clinical colleagues, including Drs. Ellsworth C. Alvord Jr (Seattle), Harm-Gerd Blaas (Trondheim), Cor Cremers and Hans Cruysberg (Nijmegen), Mark D’hooghe (Bruges), Jennian Geddes (London), Ben Hamel (Nijmegen), Frans Hoevenaars (Nijmegen), Nomdo Jansonius (Groningen), Akiyoshi Kakita (Niigata), Max Kros (Rotterdam), Hajime Miyata (Tottori), Masashi Mizuguchi (Tokyo), Reinier Mullaart,Willy Renier and Jan Rotteveel (Nijmegen), Harvey B. Sarnat (Calgary), Ben Semmekrot (Nijmegen), Waney Squier (Oxford), Sachio Takashima (Fukuoka), Rudy van Coster and Caroline Van den Broecke (Gent), Christl Vermeij-Keers (Rotterdam), Michel Willemsen (Nijmegen), and Mieko Yoshioka (Kobe). Imaging data were kindly pro-vided by Drs. Harm-Gerd Blaas (Trondheim), Berit Verbist (Leiden), John van Vugt and col-laborators (Amsterdam), Henk Thijssen and Ton van der Vliet (Nijmegen), and Guido Wilms (Leuven). Several fi gures were contributed by Drs. Jo Curfs (Nijmegen), Marieke de Heer and Jeannette Hoogeboom (Rotterdam), Raoul Hennekam (Amsterdam), Jan E. Jirasek (Prague), Enrico Marani (Leiden), Loreta Medina (Murcia), Zoltán Molnár (Oxford), Ronan O’Rahilly (Villlars-sur-Glâne), Annemieke Potters (Deventer), Kohei Shiota (Kyoto), Henny van Straaten (Maastricht), Michiel Vaandrager (Rotterdam), Jan Voogd (Oegstgeest), and Shigehito Yamada (Kyoto). Most of the drawings were made by Mrs. Marlu de Leeuw and Mr. Ad Gruter. Financial support was generously provided by the “Stichting Neurologie en Wetenschap” of the Department of Neurology (Head: Prof. Dr. George W.A.M. Padberg) and the Department of Pathology (Head: Prof. Dr. Han van Krieken), both of the Radboud University Nijmegen

viii

Medical Centre, supporting the costs of the drawings. The Japan Society for the Promotion of Science granted the fi rst author a short-term fellowship in May 2004 at the Congenital Anomaly Research Centre (Head: Prof. Dr. Kohei Shiota) of Kyoto University.

Hans J. ten Donkelaar , Nijmegen Martin Lammens , Nijmegen

Akira Hori , Toyohashi

Preface to the First Edition

ix

1 Overview of the Development of the Human Brain and Spinal Cord. . . . . . . . 1 Hans J. ten Donkelaar, Shigehito Yamada, Kohei Shiota, and Ton van der Vliet

1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2 Major Stages in the Development of the Human Brain and

Spinal Cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.3 The First 3 Weeks of Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

1.3.1 Implantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81.3.2 Gastrulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91.3.3 Folding of the Embryo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

1.4 Neurulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121.5 Development of the Spinal Cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141.6 Pattern Formation of the Brain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151.7 Early Development of the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

1.7.1 Imaging of the Embryonic Brain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181.7.2 Neuromeres . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191.7.3 The Ganglionic Eminences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

1.8 Fetal Development of the Brain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221.8.1 The Cerebellum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221.8.2 The Cerebral Cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251.8.3 Cerebral Commissures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321.8.4 Imaging of the Fetal Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

1.9 Development of the Meninges and Choroid Plexuses . . . . . . . . . . . . . . . . 331.10 Development of the Blood Supply of the Brain . . . . . . . . . . . . . . . . . . . . . 341.11 Development of Fibre Tracts

(Including Development of Myelination) . . . . . . . . . . . . . . . . . . . . . . . . . . 39References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

2 Mechanisms of Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 Hans J. ten Donkelaar

2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532.2 Neural Induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

2.2.1 The Spemann-Mangold Organizer . . . . . . . . . . . . . . . . . . . . . . . . . . . 542.2.2 The Molecular Basis of Neural Induction. . . . . . . . . . . . . . . . . . . . . . 552.2.3 Polarity and the Establishment of the Neuraxis . . . . . . . . . . . . . . . . . 562.2.4 Neural Induction in Amniote Embryos . . . . . . . . . . . . . . . . . . . . . . . . 572.2.5 Specifi c Pathways for Head Induction . . . . . . . . . . . . . . . . . . . . . . . . 57

2.3 Cell Lineage Studies and Fate Mapping. . . . . . . . . . . . . . . . . . . . . . . . . . . 592.4 Pattern Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

2.4.1 Regionalization of the Forebrain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652.4.2 The Zona Limitans Intrathalamica . . . . . . . . . . . . . . . . . . . . . . . . . . . 662.4.3 The Midbrain-Hindbrain Boundary Organizer . . . . . . . . . . . . . . . . . . 662.4.4 Segmentation of the Hindbrain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

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2.5 Neurogenesis, Gliogenesis and Migration . . . . . . . . . . . . . . . . . . . . . . . . . 692.5.1 Neurogenesis: Primary and Secondary Proliferative

Compartments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692.5.2 Gliogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 722.5.3 Migration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

2.6 Axon Outgrowth and Guidance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 772.6.1 Pioneer Fibres . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 772.6.2 The Guidance of Axons to Their Targets . . . . . . . . . . . . . . . . . . . . . . 782.6.3 Axon Guidance at Choice Points . . . . . . . . . . . . . . . . . . . . . . . . . . . . 812.6.4 Commissure Formation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 822.6.5 Formation of Thalamocortical and Corticofugal Projections . . . . . . . 832.6.6 Formation of Topographic Maps. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86

2.7 Programmed Cell Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

3 Causes of Congenital Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 Martin Lammens, John M.G. van Vugt, Michèl Willemsen,

Patrick van der Voorn, Hans van Bokhoven, and Hans J. ten Donkelaar

3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1053.2 Causes of Congenital Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

3.2.1 Genetic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106Clinical Case 3.1. Meckel-Gruber Syndrome . . . . . . . . . . . . . . . . . . . 113

3.2.2 Environmental Causes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114Clinical Case 3.2. Cytomegalovirus Encephalopathy . . . . . . . . . . . . . 118Clinical Case 3.3. Amnion Rupture Sequence . . . . . . . . . . . . . . . . . . 119

3.3 Prenatal Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1203.3.1 Ultrasound and Magnetic Resonance Examination . . . . . . . . . . . . . . 1213.3.2 Invasive Tests. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

Clinical Case 3.4. Traumatic Amniocentesis. . . . . . . . . . . . . . . . . . . . 1283.3.3 Genetic Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

3.4 Inborn Errors of Metabolism Affecting the CNS . . . . . . . . . . . . . . . . . . . 1303.4.1 Inborn Errors of Metabolism That Mainly Affect the CNS . . . . . . . . 1313.4.2 Multisystem Disorders with CNS Involvement . . . . . . . . . . . . . . . . . 132

Clinical Case 3.5. Congenital Disorders of Glycosylation . . . . . . . . . 135Clinical Case 3.6. Walker-Warburg Syndrome . . . . . . . . . . . . . . . . . . 136Clinical Case 3.7. Zellweger Syndrome . . . . . . . . . . . . . . . . . . . . . . . 137

3.5 Myelination Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139Clinical Case 3.8. Histopathological Correlates of Radial Stripes on MR Images in Lysosomal Storage Disorders. . . . . . . . . . . 140Clinical Case 3.9. X-Linked Adrenoleukodystrophy . . . . . . . . . . . . . 143Clinical Case 3.10. Vanishing White Matter Disease . . . . . . . . . . . . . 144

3.6 Vascular Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145Clinical Case 3.11. Porencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148Clinical Case 3.12. Twin-to-Twin Transfusion . . . . . . . . . . . . . . . . . . 149Clinical Case 3.13. Punctate White Matter Lesions . . . . . . . . . . . . . . 150Clinical Case 3.14. Multicystic Leukoencephalopathy. . . . . . . . . . . . 152Clinical Case 3.15. Neonatal Alloimmune Thromboctopenia . . . . . . 153Clinical Case 3.16. Vein of Galen Aneurysm . . . . . . . . . . . . . . . . . . . 154

3.7 Congenital Tumours . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155Clinical Case 3.17. Congenital Tumours: TSC . . . . . . . . . . . . . . . . . . 155

3.8 Classifi cations of CNS Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158

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4 Neurulation and Neural Tube Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 Hans J. ten Donkelaar, Mireille Bekker, Willy O. Renier,

Akira Hori, and Kohei Shiota

4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1654.2 Primary Neurulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166

4.2.1 Primary Neurulation in Chick and Mammalian Embryos. . . . . . . . . . 1664.2.2 Primary Neurulation in Human Embryos . . . . . . . . . . . . . . . . . . . . . . 170

4.3 Secondary Neurulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1734.4 Genetic Mouse Models for Neural Tube Defects . . . . . . . . . . . . . . . . . . . . 1754.5 Aetiology of Human Neural Tube Defects . . . . . . . . . . . . . . . . . . . . . . . . . 176

4.5.1 Genetic Basis: Neural Tube Defects as a Multifactorial Trait . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

4.5.2 Environmental Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1784.6 Prenatal Diagnosis and Fetal Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178

Clinical Case 4.1. Prenatal Diagnosis of NTDs . . . . . . . . . . . . . . . . . 1794.7 Cranial Neural Tube Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180

4.7.1 Anencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181Clinical Case 4.2. Ependymoblastomatous Exencephaly . . . . . . . . . . 185

4.7.2 Encephaloceles and Cranial Meningoceles. . . . . . . . . . . . . . . . . . . . . 187Clinical Case 4.3. Occipital Encephalocele . . . . . . . . . . . . . . . . . . . . 190Clinical Case 4.4. Tectocerebellar Dysraphia . . . . . . . . . . . . . . . . . . . 191Clinical Case 4.5. Cranial Meningoceles . . . . . . . . . . . . . . . . . . . . . . 192Clinical Case 4.6. Rudimentary Occipital Meningocele . . . . . . . . . . . 194

4.8 Spinal Neural Tube Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1964.8.1 Myeloceles, Myelomeningoceles and Spinal Meningoceles . . . . . . . 197

Clinical Case 4.7. The Spectrum of Deranged Neurulation . . . . . . . . 1984.8.2 Spinal Lipomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

Clinical Case 4.8. Spinal Lipomas . . . . . . . . . . . . . . . . . . . . . . . . . . . 2014.8.3 Spina Bifi da Occulta and Related Disorders. . . . . . . . . . . . . . . . . . . . 2034.8.4 The Tethered Spinal Cord Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . 203

Clinical Case 4.9. Tethered Spinal Cord Syndrome . . . . . . . . . . . . . . 2044.9 The Chiari Malformations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2054.10 Caudal Dysgenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

Clinical Case 4.10. OEIS Complex. . . . . . . . . . . . . . . . . . . . . . . . . . . 210References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211

5 The Neural Crest and Craniofacial Malformations . . . . . . . . . . . . . . . . . . . . . . 219 Hans J. ten Donkelaar, Christl Vermeij-Keers,

and Irene M.J. Mathijssen

5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2195.2 Induction and Epitheliomesenchymal Transformation

(EMT) of the Neural Crest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2205.3 Derivatives of the Neural Crest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

5.3.1 The Cranial Neural Crest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2235.3.2 The Trunk Neural Crest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

Clinical Case 5.1. Congenital Aganglionosis . . . . . . . . . . . . . . . . . . . 2275.4 Craniofacial Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228

5.4.1 Early Development of the Face . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2285.4.2 Development of the Pharyngeal Arches . . . . . . . . . . . . . . . . . . . . . . . 2305.4.3 Further Development of the Face . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2315.4.4 Development of the Skull . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236

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5.5 Neurocristopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2385.5.1 Retinoic Acid Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2395.5.2 Oculoauriculo-Vertebral Spectrum . . . . . . . . . . . . . . . . . . . . . . . . . . . 2395.5.3 Treacher Collins Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2405.5.4 DiGeorge Sequence and Related Disorders . . . . . . . . . . . . . . . . . . . . 2415.5.5 Waardenburg Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243

5.6 Cranial Ciliopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2435.7 Holoprosencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244

Clinical Case 5.2. Alobar Holoprosencephaly . . . . . . . . . . . . . . . . . . 2485.8 Abnormal Development of the Skull with CNS Manifestations. . . . . . . . 249

5.8.1 The Craniosynostoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249Clinical Case 5.3. Prenatal Diagnosis of Apert Syndrome . . . . . . . . . 254Clinical Case 5.4. Apert Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . 255Clinical Case 5.5. Thanatophoric Dysplasia . . . . . . . . . . . . . . . . . . . . 256

5.8.2 Cranial Base Abnormalities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258

6 Development and Developmental Disorders of the Spinal Cord . . . . . . . . . . . . 271 Hans J. ten Donkelaar, Kyoko Itoh, and Akira Hori

6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2716.2 Gross Development of the Spinal Cord . . . . . . . . . . . . . . . . . . . . . . . . . . . 272

6.2.1 A Few Notes on the Development of the Vertebral Column. . . . . . . . 2736.2.2 Ascensus Medullae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274

6.3 Developmental Events in Spinal Neuronal Populations . . . . . . . . . . . . . . 2756.4 The Specifi cation of Cell Fates in the Spinal Cord . . . . . . . . . . . . . . . . . . 276

6.4.1 Specifi cation of Neuronal Fates in the Ventral Spinal Cord . . . . . . . . 277Clinical Case 6.1. Spinal Muscular Atrophy. . . . . . . . . . . . . . . . . . . . 280Clinical Case 6.2. Hypoplasia of the Spinal Cord in a Case of Lethal Congenital Contracture Syndrome . . . . . . . . . . . . . . . 281

6.4.2 Patterning Cell Types in the Dorsal Spinal Cord . . . . . . . . . . . . . . . . 2826.5 Development of Dorsal Root Projections . . . . . . . . . . . . . . . . . . . . . . . . . . 2836.6 Development of Spinal Ascending Projections . . . . . . . . . . . . . . . . . . . . . 2866.7 Development of Descending Projections to the Spinal Cord . . . . . . . . . . 288

6.7.1 Descending Projections from the Brain Stem . . . . . . . . . . . . . . . . . . . 2896.7.2 Development of the Pyramidal Tract in Rodents . . . . . . . . . . . . . . . . 2916.7.3 Development of the Pyramidal Tract in Macaque Monkeys. . . . . . . . 2936.7.4 Development of the Human Pyramidal Tract . . . . . . . . . . . . . . . . . . . 294

Clinical Case 6.3. Corticospinal System Reorganization . . . . . . . . . . 297 Clinical Case 6.4. L1CAM Mutation. . . . . . . . . . . . . . . . . . . . . . . . . . 299

6.8 Developmental Anomalies of the Spinal Cord . . . . . . . . . . . . . . . . . . . . . . 2996.8.1 Anomalies of Histogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2996.8.2 Duplications of the Spinal Cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300

Clinical Case 6.5. Diplomyelia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3016.8.3 Neurenteric Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

Clinical Case 6.6. A Spinal Intradural Enterogenous Cyst . . . . . . . . . 3036.8.4 Syringomyelia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3066.8.5 Abnormal Course or Absence of Fibre Tracts. . . . . . . . . . . . . . . . . . . 307

Clinical Case 6.7. Absence of the Pyramidal Tracts . . . . . . . . . . . . . . 309Clinical Case 6.8. Anomaly of Decussation of the Pyramidal Tract in Trisomy 18 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313

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7 Development and Developmental Disorders of the Brain Stem. . . . . . . . . . . . . 321 Hans J. ten Donkelaar, Johannes R.M. Cruysberg,

Ronald Pennings, and Martin Lammens

7.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3217.2 Pattern Formation and Segmentation of the Brain Stem . . . . . . . . . . . . . 323

7.2.1 Pattern Formation of the Brain Stem. . . . . . . . . . . . . . . . . . . . . . . . . . 323Clinical Case 7.1. Agenesis of the Mesencephalon and Metencephalon with Cerebellar Hypoplasia . . . . . . . . . . . . . . . . 326

7.2.2 Segmentation of the Brain Stem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3277.3 Development and Developmental Disorders of the Cranial Nerves. . . . . 329

7.3.1 Development of the Cranial Nerves and Their Nuclei in Rodents . . . 3297.3.2 Development of Cranial Nerve Ganglia in Rodents . . . . . . . . . . . . . . 3317.3.3 Developmental and Developmental Disorders

of the Human Cranial Nerves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3317.3.4 Congenital Cranial Dysinnervation Disorders . . . . . . . . . . . . . . . . . . 332

Clinical Case 7.2. Congenital Cranial Dysinnervation Disorders. . . . 339Clinical Case 7.3. Congenital Facial Palsy . . . . . . . . . . . . . . . . . . . . . 340Clinical Case 7.4. Möbius Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . 341

7.3.5 The Sudden Infant Death Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 3437.4 Development of the Auditory System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343

7.4.1 Development of the Ear. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3447.4.2 Development of the Auditory Projections. . . . . . . . . . . . . . . . . . . . . . 3497.4.3 Developmental Disorders of the Auditory System . . . . . . . . . . . . . . . 350

Clinical Case 7.5. Pendred Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . 3527.4.4 Mutated Genes Involved in Deafness . . . . . . . . . . . . . . . . . . . . . . . . . 353

Clinical Case 7.6. Branchio-oto-renal Syndrome . . . . . . . . . . . . . . . . 359Clinical Case 7.7. Usher Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 361

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362

8 Development and Developmental Disorders of the Human Cerebellum . . . . . 371 Hans J. ten Donkelaar, Martin Lammens, Pieter Wesseling, and Akira Hori

8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3718.2 Some Notes on the Anatomy of the Cerebellum . . . . . . . . . . . . . . . . . . . . 372

8.2.1 Subdivision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3728.2.2 Compartmentalization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3738.2.3 Major Fibre Connections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3738.2.4 Precerebellar Nuclei . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374

8.3 Morphogenesis of the Cerebellum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3758.4 Four Basic Steps in the Histogenesis of the Cerebellum . . . . . . . . . . . . . . 375

8.4.1 Characterization of the Cerebellar Territory . . . . . . . . . . . . . . . . . . . . 376Clinical Case 8.1. Cerebellar Agenesis . . . . . . . . . . . . . . . . . . . . . . . . 381Clinical Case 8.2. Rhombencephalosynapsis . . . . . . . . . . . . . . . . . . . 382

8.4.2 Formation of Two Proliferative Compartments. . . . . . . . . . . . . . . . . . 3848.4.3 Inward Migration of Granule Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . 385

Clinical Case 8.3. Medulloblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . 3888.4.4 Differentiation of Cerebellar Neurons. . . . . . . . . . . . . . . . . . . . . . . . . 390

Clinical Case 8.4. Cerebello-Cortical Heterotopia in the Dentate Nucleus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392

8.5 Development of the Precerebellar Nuclei . . . . . . . . . . . . . . . . . . . . . . . . . . 3938.5.1 Upper Precerebellar System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3948.5.2 Lower Precerebellar System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3948.5.3 Inferior Olivary Malformations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395

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8.6 Mouse Mutants with Cerebellar Malformation. . . . . . . . . . . . . . . . . . . . . 3968.7 Developmental Disorders of the Cerebellum . . . . . . . . . . . . . . . . . . . . . . . 397

8.7.1 Midline or Vermis Malformations. . . . . . . . . . . . . . . . . . . . . . . . . . . . 399Clinical Case 8.5. Dandy-Walker Malformation. . . . . . . . . . . . . . . . . 403Clinical Case 8.6. Prenatal Diagnosis of DWM . . . . . . . . . . . . . . . . . 405Clinical Case 8.7. Joubert Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . 406

8.7.2 Cerebellar Hypoplasia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4088.7.3 Pontocerebellar Hypoplasias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409

Clinical Case 8.8. Pontocerebellar Hypoplasia . . . . . . . . . . . . . . . . . . 4108.7.4 Cortical Dysplasias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411

Clinical Case 8.9. Dysplastic Cerebellum with Extreme Hydrocephalus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412

9 Development and Developmental Disorders of the Forebrain. . . . . . . . . . . . . . 421 Hans J. ten Donkelaar, Martin Lammens, Johannes R.M. Cruysberg,

Karin Kamphuis-van Ulzen, Akira Hori, and Kohei Shiota

9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4229.2 Prosomeres and Pattern Formation of the Forebrain . . . . . . . . . . . . . . . . 4239.3 Development of the Diencephalon. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426

9.3.1 Development of the Thalamus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4279.3.2 Development of the Hypothalamus. . . . . . . . . . . . . . . . . . . . . . . . . . . 4339.3.3 Development of the Pituitary Gland . . . . . . . . . . . . . . . . . . . . . . . . . . 4349.3.4 Developmental Disorders of the Hypothalamus

and the Pituitary Gland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436Clinical Case 9.1 Duplication of the Pituitary Gland . . . . . . . . . . . . . 438Clinical Case 9.2 Pharyngosellar Pituitary . . . . . . . . . . . . . . . . . . . . . 439Clinical Case 9.3 Pallister-Hall Syndrome . . . . . . . . . . . . . . . . . . . . . 440

9.4 Development of the Visual System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4429.4.1 Development of the Eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4429.4.2 Congenital Malformations of the Eye. . . . . . . . . . . . . . . . . . . . . . . . . 445

Clinical Case 9.4 Aniridia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449Clinical Case 9.5 Retinitis Pigmentosa with CNS Malformations . . . 450

9.4.3 Development of the Visual Projections . . . . . . . . . . . . . . . . . . . . . . . . 450Clinical Case 9.6 Isolated Absence of the Optic Chiasm . . . . . . . . . . 453

9.5 Overview of the Development of the Telencephalon . . . . . . . . . . . . . . . . . 4539.6 Development of the Rhinencephalon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461

Clinical Case 9.7 A Remnant Olfactory Ventricle. . . . . . . . . . . . . . . . 4669.7 The Prosencephalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467

9.7.1 Aprosencephaly. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467Clinical Case 9.8 Aprosencephaly. . . . . . . . . . . . . . . . . . . . . . . . . . . . 467

9.7.2 Holoprosencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470Clinical Case 9.9 Prenatal Diagnosis of Holoprosencephaly . . . . . . . 476Clinical Case 9.10 Holoprosencephaly with Hypertrophic Olfactory Nerves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478Clinical Case 9.11 Semilobar Holoprosencephaly with a Unique Traversed Coronal Sulcus . . . . . . . . . . . . . . . . . . . . . . 479Clinical Case 9.12 Middle Interhemispheric Variant of Holoprosencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480

9.7.3 Septo-optic Dysplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482Clinical Case 9.13 Septo-optic Dysplasia . . . . . . . . . . . . . . . . . . . . . . 483

9.7.4 Isolated Arhinencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483

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9.8 Development and Developmental Disorders of the Basal Ganglia and the Amygdala . . . . . . . . . . . . . . . . . . . . . . . . . . . 4859.8.1 Development of the Basal Ganglia . . . . . . . . . . . . . . . . . . . . . . . . . . . 4859.8.2 Congenital and Acquired Disorders of the Basal Ganglia . . . . . . . . . 492

Clinical Case 9.14 Selective Vulnerability of the Basal Ganglia . . . . 496Clinical Case 9.15 Familial Striatal Degeneration (Glutaric Aciduria Type 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498Clinical Case 9.16 Leigh Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 499

9.8.3 Development of the Amygdala . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501Clinical Case 9.17 Urbach-Wiethe Disease . . . . . . . . . . . . . . . . . . . . 503

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504

10 Development and Developmental Disorders of the Cerebral Cortex . . . . . . . . 523 Hans J. ten Donkelaar, Martin Lammens, Eleonora Aronica,

Hans van Bokhoven, Karin Kamphuis-van Ulzen, and Akira Hori

10.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52410.2 Overview of the Cerebral Cortex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524

10.2.1 The Neocortex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52410.2.2 The Mesocortex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52610.2.3 The Allocortex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 528

10.3 Overview of Main Cortical Connections . . . . . . . . . . . . . . . . . . . . . . . . . . 53110.3.1 Thalamocortical Projections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53110.3.2 The Pyramidal Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53210.3.3 The Corpus Callosum and the Anterior Commissure . . . . . . . . . . . . . 53210.3.4 Long Association Fibres . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 534

10.4 Development of the Neocortex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53610.4.1 Development of the Neocortex in Rodents . . . . . . . . . . . . . . . . . . . . . 53710.4.2 Development of the Human Neocortex. . . . . . . . . . . . . . . . . . . . . . . . 543

Clinical Case 10.1 Precocious Cerebral Development . . . . . . . . . . . . 55510.5 Development of the Hippocampal Formation . . . . . . . . . . . . . . . . . . . . . . 557

Clinical Case 10.2 Temporal Lobe Dysgenesis. . . . . . . . . . . . . . . . . . 56010.6 Development of the Main Cortical Connections . . . . . . . . . . . . . . . . . . . . 561

10.6.1 Development of Thalamocortical Projections. . . . . . . . . . . . . . . . . . . 56210.6.2 Development of the Pyramidal Tract . . . . . . . . . . . . . . . . . . . . . . . . . 56210.6.3 Development of the Corpus Callosum . . . . . . . . . . . . . . . . . . . . . . . . 56210.6.4 Development of Long Association Fibres. . . . . . . . . . . . . . . . . . . . . . 566

10.7 Malformations of Cortical Development . . . . . . . . . . . . . . . . . . . . . . . . . . 56610.7.1 Malformations due to Abnormal Neuronal/

Glial Proliferation/Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567Clinical Case 10.3 Extreme Microcephaly . . . . . . . . . . . . . . . . . . . . . 571Clinical Case 10.4 Microlissencephaly . . . . . . . . . . . . . . . . . . . . . . . . 574Clinical Case 10.5: Tuberous Sclerosis Complex . . . . . . . . . . . . . . . . 575Clinical Case 10.6 Hemimegalencephaly . . . . . . . . . . . . . . . . . . . . . . 576

10.7.2 Malformations due to Abnormal Cortical Migration . . . . . . . . . . . . . 578Clinical Case 10.7 Bilateral Periventricular Nodular Heterotopia . . . 584Clinical Case 10.8 Miller-Dieker Syndrome. . . . . . . . . . . . . . . . . . . . 586Clinical Case 10.9 Subcortical Band Heterotopia. . . . . . . . . . . . . . . . 587Clinical Case 10.10 Lissencephaly with Cerebellar Hypoplasia . . . . 589Clinical Case 10.11 Walker-Warburg Syndrome. . . . . . . . . . . . . . . . . 591Clinical Case 10.12 Fukuyama-Type Congenital Muscular Dystrophy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 594

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10.7.3 Malformations due to Abnormal Cortical Organization and Late Migration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597Clinical Case 10.13 Foix-Chavany-Marie Syndrome . . . . . . . . . . . . . 598

10.7.4 Disorders of Cortical Development and Epilepsy. . . . . . . . . . . . . . . . 599Clinical Case 10.14 MCDs and Epilepsy: TSC . . . . . . . . . . . . . . . . . 603Clinical Case 10.15 MCDs and Epilepsy: FCD . . . . . . . . . . . . . . . . . 604

Clinical Case 10.16 Ammon’s Horn Sclerosis . . . . . . . . . . . . . . . . . . 60610.7.5 Vascular Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60710.7.6 Disorders of Cortical Connectivity . . . . . . . . . . . . . . . . . . . . . . . . . . . 607

Clinical Case 10.17 Assessing Prenatal White Matter Connectivity in Commissural Agenesis . . . . . . . . . . . . . . . . . . . . . . . 610Clinical Case 10.18 Callosal Agenesis . . . . . . . . . . . . . . . . . . . . . . . . 611

10.7.7 Intellectual Disability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613Clinical Case 10.19 Severe Intellectual Disability and Neuronal Migration Defects due to Mutations in DYNC1H1 . . . . . . . 617Clinical Case 10.20 Male Rett Syndrome. . . . . . . . . . . . . . . . . . . . . . 619

10.7.8 Neurobehavioural Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 623

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643

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Eleonora Aronica , M.D., Ph.D. Department of Pathology , H0-122, AMC, University of Amsterdam , Amsterdam , The Netherlands

Mireille Bekker , M.D., Ph.D. 791 Department of Obstetrics and Gynaecology , Radboud University Nijmegen Medical Centre , Nijmegen , The Netherlands

Johannes R. M. Cruysberg , M.D., Ph.D. Department of Ophthalmology , Radboud University Nijmegen Medical Centre , Nijmegen , The Netherlands

Akira Hori , M.D., Ph.D. Research Institute for Longevity Medicine, Fukushimura Hospital , Toyohashi , Japan

Institute of Pathology, Medizinische Hochschule Hannover , Hannover , Germany

Kyoko Itoh , M.D., Ph.D. Department of Pathology and Applied Neurobiology , Graduate School of Medical Science, Kyoto Prefectural University of Medicine , Kyoto , Japan

Karin Kamphuis-van Ulzen , M.D. 766 Department of Radiology , Radboud University Nijmegen MC , Nijmegen , The Netherlands

Martin Lammens , M.D., Ph.D. Department of Pathology , University Hospital Antwerpen , Edegem , Belgium

Irene M. J. Mathijssen , M.D., Ph.D. Department of Plastic and Reconstructive Surgery , Erasmus MC, University Medical Centre Rotterdam , Rotterdam , The Netherlands

Ronald Pennings , M.D., Ph.D. 377 Department of Otorhinolaryngology , Radboud University Nijmegen Medical Centre , Nijmegen , The Netherlands

Willy O. Renier , M.D., Ph.D. Rollegem-Kortrijk , Belgium

Kohei Shiota , M.D., Ph.D. Congenital Anomaly Research Center, Kyoto University Graduate School of Medicine , Kyoto , Japan

Shiga University of Medical Sciences , Otsu , Shiga Japan

Hans J. ten Donkelaar , M.D., Ph.D. 935 Department of Neurology , Radboud University Nijmegen Medical Centre , Nijmegen , The Netherlands

Hans van Bokhoven , Ph.D. 855 Department of Human Genetics , Radboud University Nijmegen Medical Centre , Nijmegen , The Netherlands

Ton van der Vliet , M.D. Department of Radiology , University Medical Centre Groningen , Groningen , The Netherlands

Patrick van der Voorn , M.D., Ph.D. Department of Pathology , VU University Medical Centre , Amsterdam , The Netherlands

John M. G. van Vugt , M.D., Ph.D. 791 Department of Obstetrics and Gynaecology , Radboud University Nijmegen Medical Centre , Nijmegen , The Netherlands

Contributors

xviii

Christl Vermeij-Keers , M.D., Ph.D. Department of Plastic and Reconstructive Surgery , Erasmus MC, University Medical Centre Rotterdam , Rotterdam , The Netherlands

Pieter Wesseling , M.D., Ph.D. 824 Department of Pathology , Radboud University Nijmegen MC , Nijmegen , The Netherlands

Michèl Willemsen , M.D., Ph.D. 935 Department of Child Neurology , Radboud University Nijmegen Medical Centre , Nijmegen , The Netherlands

Shigehito Yamada , M.D., Ph.D. Department of Anatomy and Developmental Biology , Congenital Anomaly Research Center, Kyoto University Graduate School of Medicine , Kyoto , Japan

Contributors

1H.J. ten Donkelaar et al., Clinical Neuroembryology,DOI 10.1007/978-3-642-54687-7_1, © Springer-Verlag Berlin Heidelberg 2014

1.1 Introduction

The development of the human brain and spinal cord may be divided into several phases, each of which is character-ized by particular developmental disorders (Volpe 1987 ; van der Knaap and Valk 1988 ; Aicardi 1992 ; Table 1.3 ). After implantation, formation and separation of the germ lay-ers occur, followed by dorsal and ventral induction phases, and phases of neurogenesis, migration, organization and myelination. With the transvaginal ultrasound technique a detailed description of the living embryo and fetus has become possible (Pooh and Kurjak 2009 ). With magnetic resonance imaging fetal development of the brain can now be studied in detail from about the beginning of the second half of pregnancy (Garel 2004 ). In recent years, much prog-ress has been made in elucidating the mechanisms by which the central nervous system (CNS) develops, and also in our understanding of its major developmental disorders, such as neural tube defects, holoprosencephaly, microcephaly and neuronal migration disorders. Molecular genetic data, that explain programming of development aetiologically, can now be incorporated (Sarnat 2000 ; Flores-Sarnat and Sarnat 2008 ; Barkovich et al. 2001 , 2009 , 2012 ). In this chapter an overview is presented of (1) major stages in the development of the human CNS, (2) the fi rst 3 weeks of development, (3) neurulation, (4) pattern formation, (5) early develop-ment of the brain, (6) fetal development of the brain, (7) the development of the blood supply of the brain, and (8) the development of major fi bre tracts including the development

Overview of the Development of the Human Brain and Spinal Cord

Hans J. ten Donkelaar , Shigehito Yamada , Kohei Shiota , and Ton van der Vliet

1

H. J. ten Donkelaar , M.D., Ph.D. (�) 935 Department of Neurology , Radboud University Nijmegen Medical Centre , 9101 , Nijmegen 6500 HB , The Netherlands e-mail: hans.tendonkelaar@radboudumc.nl, hjtendonkelaar@gmail.com

S. Yamada , M.D., Ph.D. Department of Anatomy and Developmental Biology , Congenital Anomaly Research Center, Kyoto University Graduate School of Medicine , Kyoto 606-8501 , Japan

K. Shiota , M.D., Ph.D. Congenital Anomaly Research Center, Kyoto University Graduate School of Medicine , Kyoto , Japan

Shiga University of Medical Sciences , Otsu , Shiga 520-2192 , Japan

T. van der Vliet , M.D. Department of Radiology , University Medical Centre , 30.001 , Groningen 9700 RB , The Netherlands

Contents

1.1 Introduction ..................................................................... 1

1.2 Major Stages in the Development of the Human Brain and Spinal Cord ........................... 2

1.3 The First 3 Weeks of Development ................................ 81.3.1 Implantation ...................................................................... 81.3.2 Gastrulation ....................................................................... 91.3.3 Folding of the Embryo ...................................................... 10

1.4 Neurulation ...................................................................... 12

1.5 Development of the Spinal Cord .................................... 14

1.6 Pattern Formation of the Brain ..................................... 15

1.7 Early Development of the Brain .................................... 171.7.1 Imaging of the Embryonic Brain ....................................... 181.7.2 Neuromeres ....................................................................... 191.7.3 The Ganglionic Eminences ............................................... 21

1.8 Fetal Development of the Brain ..................................... 221.8.1 The Cerebellum ................................................................. 221.8.2 The Cerebral Cortex .......................................................... 251.8.3 Cerebral Commissures ...................................................... 321.8.4 Imaging of the Fetal Brain ................................................ 32

1.9 Development of the Meninges and Choroid Plexuses ...................................................... 33

1.10 Development of the Blood Supply of the Brain ............ 34

1.11 Development of Fibre Tracts (Including Development of Myelination) ...................... 39

References .................................................................................... 46

2

of myelination. Mechanisms of development are discussed in Chap. 2 , and an overview of the causes of developmental malformations and their molecular genetic basis is presented in Chap. 3 . In the second, specialized part of this book the development of the CNS and its disorders are discussed in more detail.

1.2 Major Stages in the Development of the Human Brain and Spinal Cord

The human embryonic period , i.e. the fi rst 8 weeks of development, can be divided into 23 stages, the Carnegie stages (O’Rahilly and Müller 1987 ), originally described as developmental horizons (XI-XXIII) by Streeter ( 1951 ),

and completed by Heuser and Corner ( 1957 ; developmental horizon X) and O’Rahilly ( 1973 ; developmental stages 1–9). Some of the reconstructed models and drawings of the exten-sive Carnegie Collection are now archived in the Human Developmental Anatomy Center in Washington, DC ( http://nmhm.washingtondc.museum/collections/hdac/index.htm ). Important contributions to the description of human embryos were also made by Nishimura et al. ( 1977 ) and Jirásek ( 1983 , 2001 , 2004 ). Examples of human embryos, taken from the famous Kyoto Collection, are shown in Figs. 1.1 and 1.2 . In the embryonic period, postfertilization or postconcep-tional age is estimated by assigning an embryo to a develop-mental stage using a table of norms, going back to the fi rst Normentafeln by Keibel and Elze ( 1908 ). The term gesta-tional age is commonly used in clinical practice, beginning

Fig. 1.1 Dorsal views of staged early human embryos (Carnegie stages 6, 7, 9–11; from the Kyoto Collection of Human Embryos; kindly provided by Kohei Shiota)

1 Overview of the Development of the Human Brain and Spinal Cord

3

with the fi rst day of the last menstrual period. Usually, the number of menstrual or gestational weeks exceeds the num-ber of postfertilization weeks by 2. During week 1 (stages 2–4) the blastocyst is formed, during week 2 (stages 5 and 6) implantation occurs and the primitive streak is formed, fol-lowed by the formation of the notochordal process and the beginning of neurulation (stages 7–10). Somites fi rst appear at stage 9. The neural folds begin to fuse at stage 10, and the rostral and caudal neuropores close at stages 11 and 12, respectively. Gradually, the pharyngeal bars, the optic and otic vesicles, and the limb buds appear. The main external

and internal features of human embryos are summarized in Table 1.1 . The fi rst four embryonic weeks are also described as the period of blastogenesis , and the fi fth to eighth weeks as the period of organogenesis (Opitz 1993 ; Opitz et al. 1997 ). The fetal period cannot be divided into a series of morphologically defi ned stages. It is the period of phenogen-esis (Opitz 1993 ; Opitz et al. 1997 ). In the clinical literature a subdivision of the prenatal period into three trimesters of 13 weeks each is commonly used. At the junction of the trimes-ters 1 and 2, the fetus of about 90 days has a greatest length of 90 mm, whereas at the junction of the trimesters 2 and

Table 1.1 Developmental stages and features of human embryos

Carnegie stages

Length (mm)

Age (days) External features Internal features (with emphasis on the nervous system)

1 1 Fertilization 2 2–3 From 2 to about 16 cells 3 4–5 Free blastocyst Inner cell mass and trophoblast 4 6 Attaching blastocyst Cytotrophoblast and syncytiotrophoblast distinguishable 5 0.1–0.2 7–12 Implantation; embryonic disk circular Amniotic cavity; primary yolk sac; extra-embryonic

mesoderm 6 0.2 17 Embryonic disk elongated Chorionic villi; primitive streak and node; prechordal plate

appears; secondary yolk sac 7 0.4 19 Embryonic disk oval Notochordal process visible; hematopoiesis starts 8 1.0–1.5 23 Primitive pit appears; neural folds may begin

to form Notochordal and neurenteric canals detectable

9 1.5–2.5 25 First somites appear; mesencephalic fl exure begins; otic disc forms

Neural groove evident; 3 major subdivisions brain distinguishable; heart begins to develop

10 2–3.5 28 Neural folds begin to fuse; otic pit develops; 4–12 somites; pharyngeal arches 1 and 2 visible

Optic primordium begins to develop; cardiac loop appears; intermediate mesoderm

11 2.5–4.5 29 Rostral neuropore closes; 13–20 somites Optic vesicles develop 12 3–5 30 Caudal neuropore closes; 21–29 somites; 4

pharyngeal arches visible; upper limb buds appearing

Secondary neurulation starts

13 4–6 32 Otic vesicle closed; lens disc not yet indented; 30 or more somites; 4 limb buds visible

Retinal and lens discs develop; primordium of cerebellum

14 5–7 33 Lens pit appears; upper limb buds elongated Future cerebral hemispheres; pontine fl exure; optic cup develops; adenohypophysial pouch defi ned

15 7–9 36 Lens pit closed; nasal pit appearing; hand plate forming

Future cerebral hemispheres become defi ned; retinal pigment visible

16 8–11 38 Retinal pigment visible; nasal sacs face ventrally; auricular hillocks beginning; foot plate appears

Epiphysis cerebri develops; neurohypophysial evagination; olfactory tubercle

17 11–14 41 Head relatively larger; trunk straighter; auricular hillocks distinct; fi nger rays

Internal and external cerebellar swellings; chondrifi cation begins in humerus, radius and some vertebral centra

18 13–17 44 Body more cuboidal; elbow region and toe rays appearing

Oronasal membrane develops; 1–3 semicircular ducts in internal ear

19 16–18 46 Trunk elongating and straightening Olfactory bulb develops; cartilaginous otic capsule; choroid plexus of fourth ventricle

20 18–22 49 Upper limbs longer and bent at elbows Optic fi bers reach optic chiasm; choroid plexus of lateral ventricle

21 22–24 51 Fingers longer; hands approach each other, feet likewise

Cortical plate becomes visible; optic tract and lateral geniculate body

22 23–28 53 Eyelids and external ear more developed Olfactory tract; internal capsule; adenohypophysial stalk incomplete

23 27–31 56 Head more rounded; limbs longer and more developed

Insula indented; caudate nucleus and putamen recognizable; humerus presents all cartilaginous stages

After O’Rahilly and Müller ( 1987 , 2001 )

1.2 Major Stages in the Development of the Human Brain and Spinal Cord

4

Fig. 1.2 Lateral views of staged human embryos (Carnegie stages 12–23; from the Kyoto Collection of Human Embryos; kindly provided by Kohei Shiota)

3, the fetus is about 250 mm in length and weighs approxi-mately 1,000 g (O’Rahilly and Müller 2001 ; Table 1.2 ). The newborn brain weighs 300–400 g at full term. Male brains weigh slightly more than those of females but, in either case, the brain constitutes 10 % of the body weight (Crelin 1973 ).

The brain and spinal cord arise from an area of the ectoderm known as the neural plate. The folding of the neu-ral plate, leading to successively the neural groove and the neural tube, is called primary neurulation. The caudal part of the neural tube does not arise by fusion of the neural folds but develops from the so-called caudal eminence. This process is called secondary neurulation (Chap. 4 ). Before and after the surface ectoderm of the two sides fuses, the fusing neuro-

ectodermal cells of the neural folds give off the neural crest cells. The neural crest is a transient structure and gives rise to the spinal and cranial ganglia. Moreover, the whole vis-cerocranium and part of the neurocranium are formed from the neural crest (Le Douarin and Kalcheim 1999 ; Wilkie and Morriss-Kay 2001 ; Francis-West et al. 2003 ; Morriss-Kay and Wilkie 2005 ; Chap. 5 ).

Recently, remarkable progress has been made in non- destructive imaging technologies, more in particular mag-netic resonance imaging (MRI). By using a super-parallel MR microscope (Matsuda et al. 2007 ), over 1,400 human embryonic specimens have been imaged in the Kyoto Human Embryo Visualization Project (Yamada et al. 2006 , 2010 ;

1 Overview of the Development of the Human Brain and Spinal Cord

5

Fig. 1.2 (continued)

Shiota et al. 2007 ; Fig. 1.3 ). Selective images from the data-base can be viewed on the web ( http://bird.cac.med.kyoto-u.ac.jp/index_e.html ). Episcopic fl uorescence image capture is another novel method that can provide registered 2D image stacks suitable for rapid 3D rendering (Weninger and Mohun 2002 ). More recently, this technique has been used in a developmental atlas of the early fi rst trimester embryo from Carnegie stages 13 to 23 (Yamada et al. 2010 ).

The embryonic period includes three in time overlapping phases: formation and separation of the germ layers, dorsal

and ventral induction phases (Table 1.3 ). During the fi rst phase, the neural plate is formed. In the dorsal induction phase , the neural tube is formed and closed, and the three primary divisions or neuromeres of the brain (the prosen-cephalon, mesencephalon and rhombencephalon) appear. In the ventral induction phase ( telencephalization ), the cere-bral hemispheres, the eye vesicles, the olfactory bulbs and tracts, the pituitary gland and part of the face are formed. In the sixth week of development strong proliferation of the ventral walls of the telencephalic vesicles gives rise to

1.2 Major Stages in the Development of the Human Brain and Spinal Cord

6

the ganglionic or ventricular eminences. These elevations do not only form the basal ganglia but, in addition, give rise to many neurons that migrate tangentially to the cere-bral cortex. Neurogenesis starts in the spinal cord and the brain stem. Neurogenesis in the cerebellum and the cere-bral cortex occurs largely in the fetal period. The human fetal period extends from the ninth week of development to the time of birth. With regard to the prenatal ontogen-esis of the cerebral cortex, Marín-Padilla ( 1990 ) suggested to divide this long developmental period into two separate ones: (1) the fetal period proper (9–24 gestational weeks), characterized by the formation of the cortical plate; and (2) the perinatal period , extending from the 24th week of gestation to the time of birth. This period is character-ized by neuronal maturation. The separation between these two periods at the 24th week of gestation is somewhat arbitrary but may be clinically relevant. The 24th week of gestation approximates roughly the lower limit for possible survival of the prematurely born infant. Disorders of migra-tion are more likely to occur in the fetal period, whereas abnormalities affecting the architectonic organization of the cerebral cortex are more likely to occur in the perinatal period (Chap. 10 ). Kostović suggested a further subdivision of the fetal period into four developmental phases and cor-related histogenetic events with structural MRI (Kostović and Jovanov-Milošević 2006 ; Kostović and Vasung 2009 ; Chap. 10 ): (1) an early fetal phase (9–13 postconceptional weeks) with prominent proliferative zones and a trilaminar

cerebral wall; (2) a fetal phase (15–23 postconceptional weeks) with transient fetal cellular zones fully developed, a synapse-rich subplate dominating on MRI and thalamo-cortical axons accumulating below the cortical plate; (3) a preterm phase (24–36 postconceptional weeks), charac-terized by the development of gyri and sulci, thalamocorti-cal fi bres penetrating the cortical plate, persistence of the subplate, vulnerable periventricular axonal crossroads and poorly myelinated fi bre systems; and (4) a near - term phase (36– 41 postconceptional weeks) with gradual disappear-ance of transient fetal zones.

Each of the developmental phases of the brain is charac-terized by particular developmental disorders (Table 1.3 ). During the separation of the germ layers, enterogenous cysts and fi stulae may occur. In the dorsal induction phase, neural tube defects (Chap. 4 ) occur. Developmental disorders in the ventral induction phase, in which the prosencephalon is normally divided into the diencephalon and the two cerebral hemispheres, are characterized by a single, incompletely divided forebrain (holoprosencephaly; Chap. 9 ). This very heterogeneous disorder may be due to disorders of ventral-ization of the neural tube (Sarnat 2000 ; Flores-Sarnet and Sarnat 2008 ) such as underexpression of the strong ventral-izing gene Sonic hedgehog ( SHH ). During neurogenesis of the forebrain, malformations due to abnormal neuronal pro-liferation or apoptosis may occur, leading to microcephaly or megalocephaly. During the migration of the cortical neurons, malformations due to abnormal neuronal migration may

Table 1.2 Criteria for estimating age during the fetal period

Age (postconceptional weeks)

Average crown-rump length (mm)

Average foot length (mm)

Average weight (g) Main external characteristics

Previable fetuses 9 50 7 8 Eyes closing or closed; head large and more rounded; external genital not

distinguishable as male or female; intestines in proximal part of umbilical cord; low-set ears

10 61 9 14 Intestines returned to abdomen; early fi ngernail development 12 87 14 45 Sex distinguishable externally; well-defi ned neck 14 120 20 110 Head erect; eyes face anteriorly; ears close to their defi nitive position; lower

limbs well- developed; early toenail development 16 140 27 200 External ears stand out from head 18 160 33 320 Vernix caseosa covers skin; quickening felt by mother 20 190 39 460 Head and body hair (lanugo) visible Viable fetuses 22 210 45 630 Skin wrinkled, translucent, pink to red colour 24 230 50 820 Fingernails present; lean body 26 250 55 1,000 Eyes partially open; eyelashes present 28 270 59 1,300 Eyes wide open; good head of hair may be present; skin slightly wrinkled 30 280 63 1,700 Toenails present; body fi lling out; testes descending 32 300 68 2,100 Fingernails reach fi nger tips; skin pink and smooth 36 340 79 2,900 Body usually plump; lanugo hairs almost absent; toenails reach toe tips; fl exed

limbs; fi rm grasp 38 360 83 3,400 Prominent chest; breasts protrude; testes in scrotum or palpable in inguinal

canals; fi ngernails extend beyond fi nger tips

After Moore et al. ( 2000 )

1 Overview of the Development of the Human Brain and Spinal Cord

7

a b c

g h i

j k l

d e f

Fig. 1.3 MR microscopy of human embryos at different developmental stages. Human embryos at Carnegie stages (CS) 13, 16, 18 and 22 were imaged by MR microscopy. ( a , d , g , j ) Photographs of the embryos; ( b , e , h , k ) 3D reconstructions of the same embryos using MR images; ( c , f , i , l ) 2D MR images in the sagittal plane. At CS 13 ( a – c ), limb buds are present and the prosencephalon ( P ), mesencephalon ( M ) and rhomben-cephalon ( R ) with rhombomeres can be seen. Also notable is the looped heart tube ( C ). At CS 16 ( d – f ), the eye primordia and upper and lower limb buds with limb paddles are observed ( E ). In the abdominal cavity, the

midgut ( Mg ) is invested in the umbilical cord ( UC ). At CS 18 ( g – i ), anlagen for the digits are evident in the forelimb ( g , h ). In the thoracic cavity, the heart ( Ht ) and the lung are clearly seen ( i ). At CS 22 ( j – l ), cra-niofacial and eye development have advanced considerably and the digits in the fore- and hindlimbs are well developed ( l ). At this stage of develop-ment, most of the abdominal cavity is occupied by the liver ( Li ) and physi-ological midgut herniation is present ( arrowhead in l ). CF cervical fl exure, D diencephalon, PF pontine fl exure, T telencephalon, Tn tongue; bars: 1 mm (From Yamada et al. 2010 ; courtesy Shigehito Yamada)

1.2 Major Stages in the Development of the Human Brain and Spinal Cord

8

appear, varying from classic lissencephaly (‘smooth brain’), several types of neuronal heterotopia, polymicrogyria till minor cortical dysplasias. For many of these malformations, disorders of secretory molecules and genes that mediate migration have been found (Chap. 10 ). Many of these mal-formations are characterized by the presence of intellectual disability and epilepsy. Cerebellar disorders are more diffi -cult to fi t into this scheme. The Dandy-Walker malformation is thought to arise late in the embryonic period, whereas cerebellar hypoplasia presumably occurs in the fetal period. These malformations are discussed in Chap. 8 .

1.3 The First 3 Weeks of Development

During the fi rst 3 weeks of development, the three germ lay-ers (ectoderm, mesoderm and endoderm), the basis of the various organs and systems of the body, are established. During the fi rst week of development (stages 2–4), the embryo develops from a solid mass of totipotent cells or blastomeres (the morula ) into the blastocyst. This occurs when 16–32 cells are present. The blastocyst is composed of an inner cell mass or embryoblast , giving rise to the embryo, and the trophoblast , the peripherally situated cells, sur-rounding the blastocystic cavity and forming the develop-mental adnexa (Fig. 1.4 ). Embryoblast cells adjacent to this

cavity form a new layer of fl at cells, the hypoblast . This cell layer covers the blastocystic cavity from inside that is now called the primitive umbilical vesicle or yolk sac . The rest of the inner cell mass remains relatively undifferentiated and is known as the epiblast . Duplication of the inner cell mass is probably the basis for most cases of monozygotic twin-ning. Possibly, such divisions arise during ‘hatching’, the emergence of the blastocyst from the zona pellucida (O’Rahilly and Müller 2001 ). At approximately 6 days (stage 4b), the blastocyst becomes attached to the endome-trium of the uterus.

1.3.1 Implantation

The second week is characterized by implantation (stage 5) and the formation of the primitive streak (stage 6). The tro-phoblast differentiates into the cytotrophoblast and the more peripherally situated syncytiotrophoblast that invades the endometrium. Blood-fi lled spaces, the lacunae , soon develop within the syncytiotrophoblast and communicate with endo-metrial vessels, laying the basis for the placental circulation. Between the epiblast and the cytotrophoblast, the amniotic cavity appears. The embryonic disc is now known as the bilaminar embryo . Only the cylindric epiblast cells adjacent to the hypoblast form the embryo. The remaining fl attened

Table 1.3 Major stages of human CNS development

Stage

Time of occurrence (weeks) Major morphological events in brain Main corresponding disorders

Embryonic period Formation and separation of germ layers

2 Neural plate Enterogenous cysts and fi stulas; split notochord syndrome

Dorsal induction: primary neurulation

3–4 Neural tube, neural crest and derivatives; closure of rostral and caudal neuropores; paired alar plates

Anencephaly, encephalocele, myeloschisis; myelomeningocele, Chiari malformations

Ventral induction: telencephalization

4–6 Development of forebrain and face; formation of cerebral vesicles; optic and olfactory placodes; rhombic lips appear; ‘fusion’ of cerebellar plates

Holoprosencephaly; Dandy-Walker malformation; craniosynostosis

Fetal period Neuronal and glial proliferation

6–16 Cellular proliferation in ventricular and subventricular zones; early differentiation of neuroblasts and glioblasts; cellular death (apoptosis); migration of Purkinje cells and external granular layer in cerebellum

Microcephaly, megalencephaly

Migration 12–24 Migration of cortical neurons; formation of corpus callosum

Neuronal migration disorders (lissencephalies, polymicrogyria, schizencephaly, heterotopia)

Perinatal period Organization 24 to postnatal Late migration; organization and maturation of

cerebral cortex; synaptogenesis; formation of internal granular layer in cerebellum

Minor cortical dysplasias

Myelination 24 to 2 years postnatally

Myelination disorders, destructive lesions (secondarily acquired injury of normally formed structures)

Based on Aicardi ( 1992 )

1 Overview of the Development of the Human Brain and Spinal Cord

9

epithelial cells participate in the formation of the amnion (Fig. 1.4 ). The amniotic cavity is bounded ventrally by the epiblast and dorsally by a layer of amniotic ectoderm.

1.3.2 Gastrulation

During stage 6, in the slightly elongated embryonic disc cau-dally situated cells of the epiblast migrate ventralwards along the median plane, and form the primitive streak (Fig. 1.5 ). It probably appears between days 12 and 17 (Jirásek 1983 , 2001 ; Moore et al. 2000 ; O’Rahilly and Müller 2001 ). The

rostral, usually distinct part of the primitive streak is known as the primitive node of Hensen. The primitive streak is a way of entrance whereby cells invaginate, proliferate and migrate to subsequently form the extra-embryonic meso-derm, the endoderm and the intra-embryonic mesoderm. Remnants of the primitive streak may give rise to sacrococ-cygeal teratomas (Chap. 6 ). The endoderm replaces the hypoblast. The remaining part of the epiblast is the ectoderm . For this process the term gastrulation is frequently used. Originally, the term referred to the invagination of a monolayered blastula to form a bilayered gastrula, contain-ing an endoderm-lined archenteron as found in amphibians

b ca

d e

Fig. 1.4 Implantation and the formation of the bilaminar embryo: ( a ) 107-cell blastocyst; ( b – e ) blastocysts of approximately 4.5, 9, 12 and 13 days, respectively. The trophoblast and the cytotrophoblast are indicated in light red , the syncytiotrophoblast is stippled and maternal

blood in lacunae is shown in red. AC amniotic cavity, ChC chorionic cavity, eem extra-embryonic mesoderm, lc lacuna, pv primary villi, PUV primary umbilical vesicle, SUV secondary umbilical vesicle (yolk sac), us umbilical stalk (After Langman 1963 )

1.3 The First 3 Weeks of Development

10

(Chap. 2 ). Nowadays, the term gastrulation is more generally used to delimit the phase of development from the end of cleavage until the formation of an embryo possessing a defi ned axial structure (Collins and Billett 1995 ). Rostral to the primitive node, the endoderm appears thicker and is called the prechordal plate . Caudally, the epiblast is closely related to the endoderm, giving rise to the cloacal mem-brane (Fig. 1.5 ). The primitive streak is the fi rst clear-cut indication of bilaterality, so the embryo now, apart from ros-tral and caudal ends, also has right and left sides. Genetic mutations expressed in the primitive streak may lead to duplication of the neural tube (Chap. 6 ) or its partial or com-plete agenesis (Sarnat 2000 ; Flores-Sarnat and Sarnat 2008 ).

The extra - embryonic mesoderm soon covers the tro-phoblast, the amniotic ectoderm and the yolk sac (Fig. 1.4 ). Extra-embryonic mesoderm at the caudal part of the embryo forms the connecting or umbilical stalk that anchors the embryo to the chorion. The chorion is composed of the

trophoblast and the covering extra-embryonic mesoderm. Hypoblast cells and the covering extra-embryonic meso-derm form the wall of the yolk sac, whereas the amniotic epithelium and its mesodermal layer form the amnion . The secondary umbilical vesicle or yolk sac develops from the primary one, probably by collapse and disintegration of the latter (Luckett 1978 ). The yolk sac is involved in active and passive transport to the embryo, and is possibly associated with the relationship between metabolic disorders such as diabetes mellitus and congenital malformations (O’Rahilly and Müller 2001 ). The chorion encloses the chorionic cavity , in which the embryonic disk, now a trilaminar embryo , is located.

During the third and the fourth weeks, the somites, the heart, the neural folds, the three major divisions of the brain, the neural crest and the beginnings of the internal ear and the eye develop. At approximately 19 days (stage 7), rostral to the primitive streak, a prolongation below the ectoderm, the notochordal process , arises from the primitive node, and extends rostrally as far as the prechordal plate (Fig. 1.5 ). The fl oor of the notochordal process breaks down at stage 8, giving rise to the notochordal plate. The embryonic disc is now broader rostrally, and a shallow neural groove appears, which is the fi rst morphological indication of the nervous system (O’Rahilly 1973 ; O’Rahilly and Gardner 1979 ; O’Rahilly and Müller 1981 ; Jirásek 2001 , 2004 ). The primi-tive node may be hollowed by a primitive pit , which extends into the notochordal process as the notochordal canal (O’Rahilly 1973 ). The channel becomes intercalated in the endoderm, and its fl oor begins to disintegrate at once, allow-ing temporary communication between the amniotic cavity and the umbilical vesicle. The remnant of the notochordal canal at the level of the primitive pit is known as the neur-enteric canal (Fig. 1.6a ). It may be involved in the patho-genesis of enterogenous cysts (Chap. 6 ). The prechordal plate is wider than the notochordal process, and is in close contact with the fl oor of the future forebrain. The prechordal plate is derived from the prechordal mesendoderm (de Souza and Niehrs 2000 ) and it is essential for the induction of the forebrain. The prechordal plate is usually defi ned as mesendodermal tissue underlying the medial aspect of the anterior neural plate just anterior to the rostral end of the notochord.

1.3.3 Folding of the Embryo

At approximately 25 days (stage 9), folding of the embryo becomes evident. Rostral or cephalic and caudal folds over-lie the beginning foregut and hindgut, respectively (Fig. 1.6 ). Caudal to the cloacal membrane, the allantois arises as a dor-sal diverticle of the umbilical vesicle. On each side the meso-derm is arranged into three components (Fig. 1.6e ): (1) a longitudinal, paraxial band adjacent to the notochord, form-

Fig. 1.5 Dorsal ( top ) and medial ( bottom ) views of a stage 7 embryo. The ectoderm is indicated in red , the notochordal process in light red and the endoderm in grey. AC amniotic cavity, all allantois, mclo mem-brana cloacalis, nchpr notochordal process, pchpl prechordal plate, PN primitive node, PS primitive streak, SUV secondary umbilical vesicle (yolk sac), us umbilical stalk (After O’Rahilly 1973 )

1 Overview of the Development of the Human Brain and Spinal Cord

11

ing the somites; (2) intermediate mesoderm, giving rise to the urogenital system; and (3) a lateral plate , giving rise to two layers covering the body wall and the viscera, respec-tively. The fi rst layer is known as the somatopleure , the

other as the splanchnopleure . In the Anglo-Saxon literature, however, the terms somatopleure and splanchnopleure include the covering ectoderm and endoderm, respectively (O’Rahilly and Müller 2001 ). The space between the

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Fig. 1.6 The folding of the embryo: ( a , d ) Carnegie stage 8; ( b , e ) Carnegie stage 10; ( c , f ) Carnegie stage 11/12. The ectoderm ( ec ) and its derivates are indicated in red , derivates of the mesoderm ( mes ) in light red and the endoderm ( en ) in grey. AC amniotic cavity, all allantois, cem caudal eminence, dmt dermamyotome, fg foregut, hf head fold, hg hindgut, i intermediate mesoderm, IEC intra-embryonic coelom, l lateral plate of mesoderm, mclo membrana cloacalis, mes mesencephalon, mg midgut, mnp mesonephros, moph membrana oropharyngealis, nch notochord, ncr neural crest, neur neurenteric canal, ng neural groove, p paraxial mesoderm, PCC pericardiac cavity, pchpl prechordal plate, pros prosencephalon, rhomb rhombencephalon, sc spinal cord, sompl somatopleure, spchpl splanchnopleure, sptr septum transversum, SUV secondary umbilical vesicle (yolk sac), tf tail fold, ur umbilical ring, us umbilical stalk (After Streeter 1951 ; Hamilton and Mossman 1972 )

1.3 The First 3 Weeks of Development