Table Of Content2
© 2017 Mac Keith Press
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First published in this edition in 2017
British Library Cataloguing-in-Publication data
A catalogue record for this book is available from the British Library
Cover image: Sydney Crandall, a patient of Prof Kaufmann. Cover design: Hannah Rogers
ISBN: 978-1-909962-83-5
Mac Keith Press is supported by Scope
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CONTENTS
AUTHORS’ APPOINTMENTS
FOREWORD
BENGT HAGBERG : LEADING THE WAY TO RETT SYNDROME TODAY
A tribute by Dr Alan K Percy
PREFACE
PROLOGUE: PERSONAL PERSPECTIVES
My ‘Rett’ Story
Bengt Hagberg
A Mother’s Journey
Kathy Hunter
A Perspective from the British Isles
Alison Kerr
1. THE DIAGNOSIS OF RETT SYNDROME
Walter E Kaufmann and Jeffrey L Neul
2. THE NATURAL HISTORY OF RETT SYNDROME: BUILDING ON RECENT EXPERIENCE
Alan K Percy and Daniel G Glaze
3. THE CLINICAL GENETICS OF RETT SYNDROME
Hayley Archer, John Christodoulou and Angus Clarke
4. GENETIC SOURCES OF VARIATION IN RETT SYNDROME
Sonia Bjorum Brower, Helen Leonard, Francesca Mari, Alessandra Renieri and Jeffrey L Neul
5. COGNITION, COMMUNICATION AND BEHAVIOR IN INDIVIDUALS WITH RETT
SYNDROME
Gillian S Townend, Walter E Kaufmann, Peter B Marschik, Rosa Angela Fabio, Jeff Sigafoos and Leopold MG
Curfs
6. MOTOR ABNORMALITIES IN RETT SYNDROME
Jenny Downs and Teresa Temudo
7. ORTHOPEDIC ISSUES IN RETT SYNDROME
David P Roye Jr, Jenny Downs, Gordon Baikie and Brendan A Williams
8. SLEEP ISSUES IN RETT SYNDROME
Daniel G Glaze, Sarojini Budden, Yoshiko Nomura and Carolyn Ellaway
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9. EPILEPSY IN RETT SYNDROME
Andreea Nissenkorn, Maria Pintaudi, Daniel G Glaze and Bruria Ben-Zeev
10. BREATHING ABNORMALITIES IN RETT SYNDROME
Jan Marino Ramirez, Christopher Scott Ward and Jeffrey L Neul
11. GROWTH, FEEDING AND NUTRITION, AND BONE HEALTH IN RETT SYNDROME
Kathleen J Motil
12. MOLECULAR COMPLEXITIES OF MeCP2 FUNCTION IN RETT SYNDROME
Michael L Gonzales and Janine M LaSalle
13. THE NEUROBIOLOGY OF RETT SYNDROME
Walter E Kaufmann, James H Eubanks, Michael V Johnston and Mary E Blue
14. TREATMENTS FOR RETT SYNDROME: PROSPECTS FOR TARGETED THERAPIES
Wendy A Gold, SakkuBai Naidu and John Christodoulou
15. REHABILITATION IN RETT SYNDROME
Sarojini Budden
16. PERSPECTIVES IN RETT SYNDROME: WHERE WE ARE AND WHERE WE SHOULD GO
Walter E Kaufmann, Alan K Percy, Angus Clarke, Helen Leonard and SakkuBai Naidu
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AUTHORS’ APPOINTMENTS
Hayley Archer Former Consultant Clinical Geneticist, All Wales Medical
Genetics Service, University Hospital of Wales, Cardiff, UK
Gordon Baikie Honorary Research Fellow, Murdoch Childrens Research
Institute; Honorary Clinical Senior Lecturer, department of
Paediatrics, University of Melbourne, Australia
Bruria Ben-Zeev Head of Pediatric Neurology Unit & National Rett Clinic, Safra
Children Hospital, Sheba Medical Center, Tel Ha Shomer,
Sackler School of Medicine, Tel Aviv University, Israel
Mary E Blue Associate Professor of Neurology and Neuroscience, Hugo W
Moser Research Institute at Kennedy Krieger, Inc., and Johns
Hopkins University School of Medicine, Baltimore, Md, USA
Sonia Brower Senior Technical Writer, ATCC Federal Solutions, Manassas,
VA, USA
Sarojini Budden Emeritus Associate Professor, department of Pediatrics, oregon
Health and Sciences University Portland, oR, USA
John Christodoulou Head, Neurodevelopmental Genomics Research Group,
Murdoch Children’s Research Institute; Chair of Genomic
Medicine, department of Pediatrics, University of Melbourne,
Melbourne, Australia
Angus Clarke Professor of Clinical Genetics, School of Medicine, Cardiff
University, Wales, UK
Leopold MG Curfs Professor and director Governor Kremers Center and Head, Rett
Expertise Center Netherlands, Maastricht University Medical
Center, Maastricht, the Netherlands
Jenny Downs Co-Head, Child disability and Senior Research Fellow, Telethon
Kids Institute, Perth, Australia
Carolyn Ellaway Associate Professor, Clinical Geneticist, Genetic Metabolic
disorders Service, Sydney Children’s Hospital Network, Sydney
University, Australia
James H Eubanks Senior Scientist, Krembil Research Institute, University Health
Network, Toronto, ontario, Canada
Rosa Angela Fabio Professor of Experimental Psychology, department of Cognitive
Science, Psychological, Pedagogical and Cultural Studies,
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University of Messina, Italy
Daniel G Glaze Professor, departments of Pediatrics and Neurology; Medical
director, The Blue Bird Circle Rett Center, Baylor College of
Medicine, Houston, TX, USA
Wendy A Gold Senior Lecturer, Kids Research Institute, The Children’s
Hospital at Westmead, University of Sydney, Australia
Michael L Gonzales Senior Scientist, Fluidigm Corporation, Biotechnology
Company, San Francisco, CA, USA
Bengt Hagberg Emeritus Professor of Pediatrics, University of Gothenburg,
Sweden
Kathy Hunter Founder, International Rett Syndrome Association, Fort
Washington, Md, USA
Michael V Johnston Chief Medical officer and Blum Moser Endowed Chair for
Pediatric Neurology, Kennedy Krieger Institute; Professor of
Neurology, Pediatrics and Physical Medicine and Rehabilitation,
Johns Hopkins University School of Medicine, Baltimore, Md,
USA
Water E Kaufmann Ravenel Boykin Curry Chair in Genetic Therapeutics, Professor
of Neurology, Greenwood Genetic Center; Research Professor of
Pediatrics, University of South Carolina School of Medicine;
Adjunct Professor of Human Genetics, Emory University School
of Medicine, Atlanta GA, USA
Alison Kerr Honorary Clinical Senior Lecturer (Retired), Institute of Health
and Wellbeing, University of Glasgow, Scotland, UK
Janine M LaSalle Professor, Medical Microbiology and Immunology, School of
Medicine, University of California, davis, CA, USA
Helen Leonard Associate Professor, NHMRC Senior Research Fellow, Principal
Research Fellow, Telethon Kids Institute, The University of
Western Australia, Crawley, Australia
Francesca Mari Associate Professor, Medical Genetics Unit, Policlinico S. Maria
alle Scotte, Siena, Italy
Peter B Marschik Head of Interdisciplinary developmental Neuroscience; Associate
Professor, department of Phoniatrics, Medical University of
Graz, Austria; Associate Professor, Karolinska Institutet, Center
of Neurodevelopmental disorders (KINd), department of
Women’s and Children’s Health, Stockholm, Sweden
Kathleen J Motil Professor of Pediatrics, Baylor College of Medicine, Section of
Gastroenterology, Hepatology, & Nutrition, Texas Children’s
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Hospital, Houston, TX, USA
SakkuBai Naidu Professor, departments of Neurology and Pediatrics, Johns
Hopkins University School of Medicine; Research Scientist,
department of Neurogenetics Kennedy Krieger Institute,
Baltimore, Md, USA
Jeffrey L Neul Professor and Chief of division of Child Neurology, department
of Neurosciences, University of California, San diego, La Jolla,
CA, USA
Andreea Nissenkorn Head of Rare diseases Service, Pediatric Neurology Unit, Safra
Children Hospital, Sheba Medical Center, Tel Ha Shomer,
Sackler School of Medicine, Tel Aviv University, Israel
Yoshiko Nomura director, Yoshiko Nomura Neurological Clinic for Children,
Tokyo, Japan
Alan K Percy Professor, Pediatrics, Neurology, Neurobiology, Genetics, and
Psychology, University of Alabama at Birmingham School of
Medicine, Birmingham, AL, USA
Maria Pintaudi Child Neuropsychiatrist, department of Neuroscience
Rehabilitation, opthalmology, Genetics and Maternal-Infant
Sciences, University of Genoa, Italy
Jan Marino Ramirez Professor of Neurological Surgery and Pediatrics, University of
Washington School of Medicine; director, Center for Integrative
Brain Research, Seattle Children’s Hospital, Seattle, WA, USA
Alessandra Renieri Professor, department of Medical Biotechnology, University of
Siena, Italy
David P Roye Jr Professor of Clinical Pediatric orthopedic Surgery, Columbia
University Medical Center, New York, NY, USA
Jeff Sigafoos Professor, School of Education,Victoria University of
Wellington, Wellington, New Zealand
Teresa Temudo Pediatric Neurologist, Serviço de Neuropediatria, Centro
Hospitalar do Porto, Porto, Portugal
Gillian S Townend Researcher, Rett Expertise Centre-GKC, Maastricht University
Medical Centre, Maastricht, The Netherlands
Christopher S Ward Preclinical Studies Manager; Research Associate, Jan and dan
duncan Neurological Research Institute, Baylor College of
Medicine, Houston, Texas USA
Brendan A Williams Chief Resident in orthopedics, University of Florida, Gainesville,
FL, USA
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FOREWORD
Rett syndrome is an important disorder to a great many people. This is not so much because it affects several
thousand individuals worldwide (it is a rare disease), or that it results in substantial disability but because the
recognition of its complexity has paralleled fundamental developments in pediatric neurology, neurogenetics,
and neurodisability. It has become impossible to make sense of any neurodevelopmental disorder without a
thorough multi-dimensional perspective, which is ably demonstrated in this book. In addition to accurate, up-
to-date information about every aspect of Rett syndrome, regarding both basic understanding and clinical
management, this timely volume provides messages that may serve as guiding principles across a wide array of
neurological conditions.
As described in the Prologue, the characterisation of Rett syndrome originated in self-confident, clinical
observation: Andreas Rett observed facts (i.e. empirical data) and in the face of incomplete knowledge, made a
situational judgement that the girls he had observed who showed stereotypical hand movements and other
signs shared a specific syndrome that had not been described previously. This approach remains at the core of
all good medical practice.
The same scenario was repeated by other clinicians in Japan, Sweden and elsewhere until the syndrome
gained wide recognition in the medical world. The phenotype of Rett syndrome was refined to suggest
diagnostic criteria, update them based on better observation, and pave the way to the discovery of its biological
basis. A breakthrough in this process was the demonstration of MECP2 mutations, with crucial implications
for diagnosis and new questions on pathophysiology, many of them still unanswered. Thus, Rett syndrome
became the first neurodevelopmental disorder related to defective transcription of methylated DNA.
Importantly, those clinicians recognised the value of behavioural manifestations by characterising the
association of the cognitive, language, social skills, and motor control features that constitute the behavioural
phenotype of Rett syndrome. The behavioural phenotype of conditions that were described around the time of
Andreas Rett’s first observations (e.g. Williams syndrome [1961], Lesch–Nyhan syndrome [1964], or
Angelman syndrome [1965]), remain highly relevant to current clinical practice, in particular with regard to
diagnosis, management, and outcome measures.
Yet the clinical course of Rett syndrome poses a challenge to the classic distinction between
neurodevelopmental disorders, in which a brain defects cause symptoms from birth, and neurodegenerative
disorders in which progressive, life-limiting changes induce the gradual loss of acquired skills. In Rett
syndrome, most infants do not show any obvious developmental problems. After a few months, however,
severe regression occurs, together with a delay in acquiring new skills, emergence of autistic features, loss of
purposeful manipulation skills replaced by stereotyped hand movements, ataxia and apraxia, while no neuronal
degeneration explains the change. This has led clinicians to consider development and neurodevelopmental
disorders in a more complex way than the linear approach that has long prevailed in the field. Several models
have been suggested to explain the ‘natural history’ of Rett syndrome, from arrested development to stage
systems, though the current trend tends to focus on individual developmental trajectories, activities of daily
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