Neuromuscular disorders of infancy, childhood, and adolescence : a clinician's approach

1118 Pages·2014·143.776 MB·English

by  Basil T Darras, H Royden Jones, Monique M Ryan, Darryl C De Vivo

Neuromuscular Disorders of Infancy,
Childhood, and Adolescence
A Clinician’s Approach
Neuromuscular Disorders
of Infancy, Childhood, and
Adolescence
A Clinician’s Approach
Second Edition
Edited by
Basil T. Darras, MD
Joseph J. Volpe Professor of Neurology, Harvard Medical School, Associate Neurologist-in-Chief,
Chief, Division of Clinical Neurology, Director, Neuromuscular Program,
Boston Children’s Hospital, Boston, Massachusetts, USA
H. Royden Jones, Jr., MD
Jaime Ortiz-Patino Chair in Neurology, Lahey Clinic, Burlington, Massachusetts
Clinical Professor of Neurology, Harvard Medical School, Director Emeritus,
Electromyography Laboratory, Boston Children’s Hospital, Boston, Massachusetts, USA, d. 2013
Monique M. Ryan, M Med BS, FRACP
Associate Professor, Paediatric Neurologist, Children’s Neurosciences Centre, Research Fellow,
Murdoch Childrens Research Institute, Clinical Associate Professor, University of Melbourne,
Royal Children’s Hospital, Victoria, Australia
Darryl C. De Vivo, MD
Sidney Carter Professor of Neurology Professor of Pediatrics
Associate Chairman (Neurology) for Pediatric Neurosciences,
Director, Pediatric Neurology, Emeritus Director, Colleen Giblin Research Laboratories,
Director, Pediatric Neuromuscular Disease Center, Co-Director,
Center for Motor Neuron Biology and Disease,
Columbia University Medical Center, The Neurological Institute, New York,
New York, USA
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Dedication
The editors dedicate this book to the man who was the Tomylateparents,TheodoreandAnastasia,forinstilling
architect of the first edition and the inspiration for the sec- in me intellectual curiosity and ambition; and to my
ond.RoyJoneswasanexcellentphysician,acaring,gener- daughters,NatashaandIrene-Olympia,foryourgenuinelove.
ous and inspiring teacher to a generation of neurologists, (cid:1)BasilT.Darras
and respected by professionals around the world. Most of
all,Roywascherishedasadearfriend,avalued colleague, To my husband Peter, with gratitude for your generosity,
andalovinghusbandandparent.Hiscourage,endlessopti- support and love, for Annabel and Campbell who I love
mismandinfectiousenthusiasmwillalwaysberemembered dearly,andforPatrick,whowillonedayreadthisbookand
bythoseofusfortunateenoughtohaveknownandworked wonderhowyoucouldwritesuchalongbookwithoutput-
withhim. tinginanydragonsatall.
The editors wish to acknowledge the late Julianna (cid:1)MoniqueM.Ryan
Wittre´di of Geneva, Switzerland, whose elegant drawings
of the Gowers maneuver appear on the book’s front and To Kristin, Jessica, Cynthia and Alicia for your continuing
back covers. Mrs. Wittre´di, the mother of contributing love, support and understanding; and to the memory of our
authorDr.CarolineMenache-Starobinski,passedawaydur- daughter Alicita, who left us on Resurrection Sunday for a
ingthepreparationofthisedition,notknowingthatherart- betterplace.
workwouldgraceourcover. (cid:1)DarrylC.DeVivo
ABOUT THE COVER IMAGES
Front cover: Top: Gowers figure by Julianna Wittre´di of Geneva, Switzerland. Bottom four figures: Muscle biopsies
have been immunostained with a combination of antidystrophin (DYS2) and ankyrin 1 (ANK1) antibodies; the latter
stain the sarcomere green. Figures courtesy of Matthew Alexander, PhD, Division of Genetics, Boston Children’s
Hospital.
Backcover:GowersfigurebyJuliannaWittre´diofGeneva,Switzerland.
Foreword
This foreword to the second edition should begin with a geneticist. His understanding of the molecular genetics of
heartfelt testimonial to the founder of this book, the late disorders of the neuromuscular system is broad and deep
Dr. Roy Jones. Roy was a personal friend and colleague and ensures that the explosion of molecular genetics into
for more than 20 years, and his larger-than-life personal- this field is an intricate part of this book. His extensive
ity and dedication to everything that is good in medicine experience with children, gained at Boston Children’s
wasasourceofinspirationandadmirationforallofus. Hospital in Massachusetts is unparalleled anywhere. The
The symptoms and signs of neuromuscular disease late Dr. Jones brought his extraordinary skills in clinical
are extraordinarily common in infancy, childhood, and assessment and in electrophysiological studies of muscle,
adolescence. Hypotonia in the infant, weakness in the nerve, neuromuscular junction, and anterior horn cell. His
child, and cramps in the adolescent are only a few of indelible stamp on the book remains. Dr. Ryan, who
the complaints frequently encountered. Indeed, in gen- benefited greatly from the mentorship of Dr. Jones and
eral pediatric practice, apparent disturbances of neuro- Dr. Darras, brings her considerable clinical strengths,
muscular function are among the most frequent reasons especially in the many facets of peripheral nerve disor-
for consultation, and the pediatrician is often faced with ders. Dr. De Vivo is a world leader in child neurology
vexing questions concerning the appropriate detail of the and, in particular, in metabolic disorders and their impact
evaluation. As a consequence, referral to neurological on the neuromuscular system. His exceptional knowledge
specialists for evaluation of such symptoms of neuro- of the complex interactions in the biochemical pathways
muscular disease is very common indeed. Therein lies of glucose, fatty acid, and mitochondrial metabolism in
the need for a comprehensive text, with detail and neuromuscular diseases has provided this book with
sophistication for the specialist as well as practical clini- uniquestrengthsinthiscrucialaspectofthefield.
cal insights for the primary physician. Such a single The organization, topics, and authors chosen for the
source became available with the first edition of this second edition of Neuromuscular Disorders of Infancy,
book. Several excellent monographs on anterior horn Childhood, and Adolescence are superb. Thus, rather than
cell disease, peripheral neuropathies, and related neuro- plodding in an encyclopedic fashion through every dis-
muscular disorders in children have been published, and ease, the book begins with five excellent chapters on the
comprehensive textbooks on neuromuscular disorders in clinical approach, modern genetics, EMG, muscle biopsy,
adults are also available. However, this marvelous book, and nerve biopsy. After overviews of the evaluation of
the current edition co-edited by Drs. Darras, Ryan and the “floppy infant” and the infant with arthrogryposis, the
De Vivo with important initial contributions by Roy book then is organized logically in major sections based
Jones before his untimely passing, fills the need for a on the anatomical level of the disorder. Within these sec-
comprehensive, state-of-the-art text on “Neuromuscular tions, the specific categories of disease are described in
Disorders of Infancy, Childhood, and Adolescence” in depth. The book concludes with a superb section on ther-
an extraordinary manner. apyinneuromusculardisorders.
The co-editors are extremely well-suited for the task The authors who have contributed to this book are
of preparing this comprehensive text, and, indeed, their extraordinary. The list reads like a “who’s who” in mod-
skills complement each other very effectively. Dr. Darras ern neuromuscular disease. The co-editors are to be con-
brings the strengths not only of a superb clinical child gratulated for enlisting the best. The individual chapters
neurologist with a focus on neuromuscular disease, but, are superbly written and edited, such that the approach is
additionally, the skills of a fully trained and certified uniform and up-to-date. Appropriate emphasis is placed
xxiii
xxiv Foreword
on the impact of molecular genetics on understanding of edition should firmly establish this book as the bible of
pathogenesis,diagnosis,andtherapy. thefield.
This book will have a very broad audience. Primary JosephJ.Volpe,MD
physicians,neurologists,neuromuscularexperts,residents, BronsonCrothersDistinguishedProfessorof
and fellows will learn very much from this volume. The Neurology,HarvardMedicalSchool,
great success of the first edition and the amplifications, Neurologist-in-ChiefEmeritus
elaborations and state-of-the-art updating of the current BostonChildren’sHospital,Boston,
Massachusetts,USA
Preface to the Second Edition
More than a decade has passed since the first edition of between the bench and the bedside. The genotype, as
this textbook was published. Since 2003, much has hap- defined by next generation sequencing, is an equalpartner
pened in medicine and science, and in publishing. Simply with the clinical phenotype, as defined traditionally by
stated, these professions have been transformed: medicine careful clinical evaluation. This dynamic interplay is
and science by the explosion of molecular genetics, and equivalenttothenature-nurturestoryinneuroscience;itis
publishing by the explosion of the Internet and social noteither-or,butboth.Asaresult,theprofessionalexperi-
media. These transformations have been equivalent to ence is much more rewarding and demanding, and our
forces of nature; and understandably, these forces have patients will be the ultimate beneficiaries. Neurologists
been imposed upon the architects of the second edition of nowhavetheopportunitytotruncatethe“diagnosticodys-
this textbook, the editors, the contributors, and the sey”andinfactdiagnoseanindividualbeforetheonsetof
publisher. clinical symptoms. These advances do not make the prac-
As we said in the Preface to the First Edition, “We tice of neurology easier; they simply change the paradigm
[the editors and contributors] have learned other lessons and introduce new challenges. They do mean that we can
while assembling thistextbook.” We can restatethis com- doourjobforthepatientevenmoreeffectively,moreeffi-
ment today as we complete the second edition, but this ciently,andhopefullymorecost-effectively.Thecontribu-
time punctuated with an exclamation point! Physicians torshavedoneasuperbjobincapturingandincorporating
andacademiciansarepulled inmoredirectionstodaythan these scientific advances into their revised or new chap-
ever before, even though each present day has the same ters,ofwhichthereare54inthissecondedition.
number ofminutes aspast days. Itis increasingly difficult Neuromuscular disorders are a diverse group of con-
to find the time to review and reflect on the burgeoning ditions that affect one in 2000 children worldwide. We
literature, both old and new, because of the greater now know the genetic basis of more than 40 muscular
demands imposed upon us. The days seem longer, the dystrophies, 38 congenital myopathies, 25 congenital
nights shorter, and the information overload simply myasthenic syndromes, 26 metabolic myopathies, and 75
exhausting. And the reason for these feelings is the hereditary motor and sensory neuropathies, to name just
exploding universe of information. We seem to be a few of the disease categories seen by the child neurol-
“drowning”in this sea of information, desperately inneed ogist. Clinicians now routinely access novel next-
of management strategies that will allow us to capitalize generation sequencing techniques, resulting in rapid
on the flood of new ideas and knowledge and thereby identification of new syndromes and, in many cases,
care for our patients in more efficient and effective ways. expansion of our understanding of the molecular basis of
This reality has been the main challenge presented during known conditions. This improved understanding has led
the preparation of the second edition of this textbook, and to the development of specific therapies for some dis-
we believe the contributors have risen to this challenge. eases. Enzyme replacement therapy, immunosuppression,
They have achieved the editors’ primary goal of the and cofactor or vitamin supplementation are now revers-
second edition: to maintain focus on the patient, empha- ing or significantly ameliorating potentially devastating
sizing the clinical approach through, for example, one of neuromuscular disorders of childhood. Gene therapy and
the signatures of the first and second editions, the clinical other molecular-based therapeutic strategies are now
vignettesthat“humanize”thetext. entering our clinics as treatments for spinal muscular
We also recognize the importance of the extraordinary atrophy, the dystrophinopathies, and other genetically
scientific advances of the past decade and melding these determined neuromuscular diseases. For many other dis-
advances with the rich clinical experience and history sur- eases, specific therapeutics remain on the horizon but are
rounding the field of neuromuscular diseases. The practice likely to become realities before the third edition of this
ofmedicinetodayistrulytranslational,adynamicinterplay textbook is published. These are truly exciting times.
xxv
xxvi PrefacetotheSecondEdition
The identification of specific syndromes and develop- truly has been a labor of love, and a measure of our com-
ment of new therapies for pediatric neuromuscular disor- mitment to the patients we serve. Shaye Moore and
ders has, in the last decade, been facilitated by expanded Elizabeth Jarvis, from the Career Development and
collaborations among medical centers throughout the Medical WritingTeamoftheDepartmentofNeurologyat
world, as well as collaborations among patient and parent Boston Children’s Hospital, have provided hundreds of
support groups, academia, industry and government. hours of outstanding editorial support, and have been
These collaborations by the diverse stake-holders in the patient, efficient, dedicated and exacting in their invalu-
US, Europe and other continents have standardized clini- able contributions to the editing process of each of the 54
cal care, advanced outcomes research, improved clinical chapters in this book. Dr. Darras is grateful for the assis-
trial design, and led to the establishment of disease regis- tance of Jenan D’Isola at Boston Children’s Hospital, and
tries. These synergistic initiatives have accelerated the Dr. De Vivo for the assistance of Rosangel Cruz of
searchforeffectivetherapiesandharmonizedthestandard Columbia University Medical Center. From Elsevier, we
of care across the world in a way that could not have acknowledge with thanks the assistance provided by Mica
been anticipated when the first edition of this book was Haley, Publisher, Neuroscience, and Kristi Anderson,
published. Editorial Project Manager. Significant funding for this
Thevalueinthesemodernadvances dependsonastute effort was provided to Dr. Darras from the Joseph J.
clinicians who are the first to examine the symptomatic VolpeChairfundatBostonChildren’sHospital.
child, and who are conversant with all of the diagnostic Sadly, some authors from the first edition of this text-
and therapeutic tools at their disposal. This textbook is book were not able to contribute to this edition. We note
written for such physicians and therapists involved in the with sadness the passing of our respected colleagues
day-to-day care of children with neuromuscular disorders, Guillermo A. Suarez, Asa Wilbourn, John W. Griffin, and
who share the ultimate goal of improving their multidisci- Hugo Moser, and we acknowledge with gratitude their
plinary care and rescuing patients therapeutically from great wisdom and their outstanding, long-lasting contribu-
theirdiseaseswheneverpossible. tionstothefield.
Each chapter has been prepared by experts in the area, Finally, during the preparation of this textbook
and we are very grateful to our many colleagues and H. Royden Jones, Jr., editor-in-chief of the first edition
friendsfortheirgenerosityinsharingtheirknowledgeand andthedrivingforcebehindthisnewedition,diedofpan-
expertise for this textbook. Every first edition chapter in creatic cancer. Anyimportantaccomplishment mustbegin
this book has required significant revisions or extensive withanoriginal idea,andtheideaofatextbookdedicated
rewriting, and every new chapter similarly reflects the to pediatric neuromuscular diseases emerged from Roy’s
extent of scientific progress in the last 11 years, often creative mind. Roy was an outstanding clinician who
shifting the focus from clinical diagnosis, to molecular defined the field of neurophysiologic evaluation of neuro-
mechanisms,toexcitingnewtherapies. muscular function in children. He wrote or co-wrote most
Some of these changes since the first edition have of the seminal works in his area, and was a teacher,
been truly breathtaking: witness just one example, friend, and mentor to many of the experts who have con-
Duchenne muscular dystrophy. Our improved understand- tributed to this book. The impact of his contribution is
ing of this disorder has forced us to expand the relevant reflected in the number of references to his papers in
sections in this book, devoting specific chapters to diag- these chapters. He was a dedicated clinician and a won-
nosis,clinicalmanagement,andclinicaltrials.Thecurrent derful neurologist. Although not a pediatrician by train-
emphasis on clinical trials and novel therapeutics has ing, he loved working with children. One might say that
prompted us to devote a new chapter to translational he was “a natural,” comfortably interacting with children
researchintoneuromusculardisorders.Wehopethatthese and their parents and leaving them with a feeling of hope.
changes in focus are of value in providing a detailed He had a wonderful sense of humor and great personal
backgroundtoarapidlychangingfield. warmth,andwillalwaysbemissedbythoseluckyenough
Textbooks such as this take much work. The editors tohaveknownhim.
have dedicated hours to this book, competing with
time otherwise spent caring for patients, teaching stu- BasilT.Darras,Editor-in-Chief
dents, or enjoying quality time with our families. We MoniqueM.Ryan
acknowledge with gratitude the support of our collea- DarrylC.DeVivo
gues,fellows,spouses,andchildren.Withouttheirselfless Boston,Melbourne,andNewYork
understanding, this work could not have been finished. It September2014
Preface to the First Edition
Thehypotonicinfantandtheweakchildhavecapturedthe stage of the evolution of this book, we recognized the
attention of physicians for centuries. In many ways, the enormityofthecollective inputofourcolleaguesoverthe
seminal reports of Duchenne, Werdnig, and Hoffmann, past several decades. We wanted this volume to be com-
and many others have served as the historical underpin- prehensive, covering the child’s neuromuscular system,
nings of the modern discipline of childhood neuromuscu- andparticularlyclinicallycomplete,focusingontreatment
lar disorders as we currently appreciate them. A detailed issues, rehabilitation, and bioethics. To be sure, a text-
knowledge of molecular neurogenetics and protein chem- book that focuses primarily on the pediatric domain
istryisnowessentialforourcomprehensionofthenumer- would still inevitably overlap with some existing text-
ous disorders resulting from alterations of the dystrophin books that cover similar clinical material. But we were
complex or the survival motor neuron (SMN) complex. determinedtohaveouremphasisdiffer.
And it does not end there—witness the extraordinary The clinical perspective is captured in the numerous
advances of the past decade in our understanding of the case examples that appear throughout most of the 65
many disease mechanisms underlying the inherited and chapters. Each of these vignettes allows the student of
acquired neuropathies, disorders of neuromuscular trans- this medical discipline to appreciate the clinical presenta-
mission, and other myopathies. The rapidly expanding tion inthe classical sense, orincertain instances the diffi-
knowledge base related to the limb-girdle myopathies and culty initially making a correct diagnosis. Many of these
the hereditary motor and sensory neuropathies has been case examples represent clinical descriptions taken from
nothingshortofspectacular. the first published reports in an effort to be faithful to the
Early on, this clinical discipline was captured partly in original observations. Hopefully, as pediatric physicians,
the writingsof several scholars within the field. And what we will always start with the child andend with the child,
we know today is the product of a collective effort by a cycle that takes us from the bedside to the bench and
manyphysiciansandscientistswhohavelaboredtirelessly back to the bedside. Additionally, very important ethical
onbehalfofthemanychildrenafflictedwithneuromuscu- issues are now receiving their long overdue emphasis in
lardisorders.Althoughthereareafewwell-respectedindi- many medical formats. These are especially germane to
vidual textbooks dedicated to specific portions of the the care of children with many neuromuscular disorders.
child’speripheralmotorunit,theseconcentrateonjustone The multiple new diagnostic genetic tests, as well as the
area, such as motor neuronopathies, peripheral neuropa- splendid advances in intensive care management, add to
thies, or myopathies. Each of the editors of this text, the complex bioethical issues confronting the physician
early on and subsequently in our careers, appreciated and the parents of the child with many forms of pediatric
the lack of a comprehensive and substantial textbook of neuromuscular disorders. These sometimes challenge our
neuromuscular disorders dedicated to the pediatric per- societal mores, as discussed in the concluding chapter of
spective. Therefore, child and adult neurologists, pediatri- this monograph. Overall congenital issues and develop-
cians, orthopedic surgeons, and rehabilitation medicine mental nuances are given primary attention in this mono-
specialistshaveoftenneededtoseekspecificseminalindi- graph, whereas adult disorders, such as amyotrophic
vidual papers from the pediatric literature. Unfortunately, lateral sclerosis, are discussed only when there is an
in this setting the practitioner is often left uncertain, both instructive lesson that can be applied toits very rare pedi-
to the science and the precise clinical approach, despite atricpresentation.
having a well-known expert’s opinion in this ever- Many of our colleagues have been called upon to help
expandingfieldofpediatricneuromusculardisorders. us develop this text. We are greatly indebted to each of
Therefore,wesetouttoachieveourgoal—theproduc- them for their very enthusiastic support. These world-
tion of a textbook that concentrates on all aspects of neu- renowned clinicians and neuromuscular researchers have
romuscular disorders presenting in infancy, childhood, provided a very broad perspective for the reader. Their
and adolescence. Prior to and concomitantly at an early chapters provide the child’s physician with an in-depth
xxvii