Spectrums of Amyotrophic Lateral Sclerosis E-Book
107,99 €
Mehr erfahren.
- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
SPECTRUMS OF AMYOTROPHIC LATERAL SCLEROSIS Discover state-of-the-art research findings on ALS from leading authors and editors in the field In Spectrums of Amyotrophic Lateral Sclerosis: Heterogeneity, Pathogenesis & Therapeutic Directions, distinguished researchers and editors Dr. Christopher A. Shaw and Jessica R. Morrice deliver a practical and powerful perspective on Amyotrophic Lateral Sclerosis (ALS) as a heterogeneous spectrum of disorders. This increasingly accepted point-of-view allows researchers and medical professionals to develop better targeted interventions and more precise therapies. In the book, readers will find chapters on a wide variety of critical issues facing ALS researchers and healthcare practitioners treating ALS sufferers, including animal models of ALS, neuronal support cells known to have a pivotal role in ALS, and current challenges in ALS clinical trials, among others. The authors describe pathologic features common to all cases of ALS and why animal models, though crucial, should be interpreted with caution. Finally, multiple genetic and environmental etiologies of the disease are discussed. Readers will also benefit from the inclusion of: * A thorough introduction to ALS as a spectrum disease and the implications for models, therapeutic development and clinical trial design * Explorations of the genetic basis of ALS, prospective sALS etiologies, and the involvement of microbiome in ALS * Discussions of ALS-PDC and environmental risk factors, protein aggregation in ALS, defects in RNA metabolism in ALS, and the non-cell autonomous nature of ALS and the involvement of glial cells * Examinations of animal models of ALS and perspectives on previously failed ALS therapeutics and current therapeutic strategies Perfect for clinical neurologists, healthcare providers and caretakers, clinicians, and researchers studying motor neuron disease, Spectrums of Amyotrophic Lateral Sclerosis: Heterogeneity, Pathogenesis & Therapeutic Directions is also an indispensable resource for the neurodegenerative research community, neurology residents, and graduate-level neuroscience students.
Sie lesen das E-Book in den Legimi-Apps auf:
Seitenzahl: 465
Veröffentlichungsjahr: 2021
Ähnliche
Table of Contents
Cover
Title Page
Copyright Page
Dedication Page
Contributors
Foreword
Preface
Acknowledgments
CHAPTER 1: Clinical Heterogeneity of ALS – Implications for Models and Therapeutic Development
INTRODUCTION
CLINICAL HETEROGENEITY OF ALS
PLEIOTROPY OF ALS GENES
GENETIC MODELS TO STUDY ALS
CONCLUSION
CONFLICT OF INTEREST
COPYRIGHT AND PERMISSION STATEMENT
REFERENCES
CHAPTER 2: Genetic Basis of ALS
INTRODUCTION
GENES CAUSING ALS
RECENTLY DISCOVERED GENES
ASPECTS OF ALS HERITABILITY
NONCODING VARIATION
CONCLUSIONS
ACKNOWLEDGMENTS
CONFLICT OF INTEREST
COPYRIGHT AND PERMISSION STATEMENT
REFERENCES
CHAPTER 3: Susceptibility Genes and Epigenetics in Sporadic ALS
INTRODUCTION
ENVIRONMENTAL ASSOCIATIONS IN sALS
GENETIC BASIS OF sALS
IDENTIFICATION OF sALS SUSCEPTIBILITY GENES
CANDIDATE sALS SUSCEPTIBILITY GENES
EPIGENETIC MECHANISMS IN sALS
MODIFICATIONS TO THE EPIGENOME BY ENVIRONMENTAL FACTORS
CONCLUSION
CONFLICT OF INTEREST
COPYRIGHT AND PERMISSION STATEMENT
REFERENCES
CHAPTER 4: The Lessons of ALS‐PDC – Environmental Factors in ALS Etiology
INTRODUCTION
KOCH'S POSTULATES IN THE SEARCH OF ETIOLOGICAL ALS FACTORS
NEUROLOGICAL DISEASE CLUSTERS
THE NATURAL HISTORY OF ALS‐PDC
INVESTIGATING ETIOLOGICAL FACTORS
IDENTIFIED CYCAD TOXIN/TOXICANTS
ALUMINUM AND IONIC ETIOLOGIES FOR ALS‐PDC
OTHER MOLECULES THAT MIGHT HAVE BEEN INVOLVED IN ALS‐PDC
A PUTATIVE VIRAL ETIOLOGY FOR ALS‐PDC ON GUAM AND ALS IN GENERAL
THE CONTINUING IMPORTANCE OF ALS‐PDC
SUMMARY AND CONCLUSIONS
ACKNOWLEDGMENTS
CONFLICT OF INTEREST
COPYRIGHT AND PERMISSION STATEMENT
REFERENCES
CHAPTER 5: The Microbiome of ALS – Does It Start from the Gut?
INTRODUCTION
RECENT STUDIES
HOW COULD THE MICROBIOME CONTRIBUTE TO ALS?
MICROBIOME MODULATION AS A POTENTIAL THERAPEUTIC AVENUE
CONCLUSION
CONFLICT OF INTEREST
COPYRIGHT AND PERMISSION STATEMENT
REFERENCES
CHAPTER 6: Protein Aggregation in Amyotrophic Lateral Sclerosis
INTRODUCTION
PATHOLOGICAL PROTEIN INCLUSIONS ASSOCIATED WITH ALS
CONSEQUENCES OF PROTEIN AGGREGATION IN ALS
THE PRIMARY AGGREGATING PROTEINS IN ALS
PRION‐LIKE PROPAGATION OF PROTEIN AGGREGATION IN ALS
CONCLUSION
ACKNOWLEDGMENTS
CONFLICT OF INTEREST
COPYRIGHT AND PERMISSION STATEMENT
REFERENCES
CHAPTER 7: Evidence for a Growing Involvement of Glia in Amyotrophic Lateral Sclerosis
INTRODUCTION
NON‐NEURONAL CELLS PLAY IMPORTANT ROLES IN NEURODEGENERATION INCLUDING IN ALS
GLIAL ACTIVATION IN ALS MODELS
GLIAL INCLUSION FORMATION IN ALS
THE ROLE OF GLIAL CELLS IN SOD1 PATHOLOGY MIGHT BE DIFFERENT FROM OTHER FORMS OF ALS
CONCLUSION
ACKNOWLEDGMENTS
CONFLICT OF INTEREST
COPYRIGHT AND PERMISSION STATEMENT
REFERENCES
CHAPTER 8: Animal Models of ALS – Current and Future Perspectives
INTRODUCTION
THE CLINICAL MANIFESTATIONS OF ALS
CURRENT AND EXPERIMENTAL PHARMACOLOGICAL INTERVENTIONS
CAUSATIVE FACTORS IN THE DEVELOPMENT OF ALS
ANIMAL MODELS OF ALS
FUTURE MODEL DEVELOPMENT
ACKNOWLEDGMENTS
CONFLICT OF INTEREST
COPYRIGHT AND PERMISSION STATEMENT
REFERENCES
CHAPTER 9: Clinical Trials in ALS – Current Challenges and Strategies for Future Directions
INTRODUCTION
CHALLENGES IN ALS CLINICAL TRIALS
DISEASE HETEROGENEITY
LACK OF ESTABLISHED BIOMARKERS
LIMITATIONS OF CONVENTIONAL OUTCOME MEASURES
PHASE II TRIAL “PARADOX”
PATIENT RECRUITMENT AND RETENTION
ASSUMPTIONS FOR LEAD‐IN PHASES
NAVIGATING REGULATORY NUANCES
FUTURE DIRECTIONS
ADVANCES IN DISEASE UNDERSTANDING AND ASSESSMENT
NEW APPROACHES TO TRIAL DESIGN
EDUCATION
PEOPLE MAKE OR BREAK A TRIAL
ACKNOWLEDGMENTS
CONFLICT OF INTEREST
COPYRIGHT AND PERMISSION STATEMENT
REFERENCES
CHAPTER 10: Future Priorities and Directions in ALS Research and Treatment
INTRODUCTION
ETIOLOGICAL HETEROGENEITY OF ALS
ALS RISK FACTORS
CELLULAR DYSFUNCTION IN ALS
ALS AS A “TREATABLE” DISEASE
THE IMPORTANCE OF EFFECTIVE BIOMARKERS
FUTURE THERAPEUTIC AVENUES FOR A HETEROGENEOUS DISEASE
ONGOING CLINICAL TRIALS USING CuATSM
CONCLUSIONS AND THE ROAD FORWARD IN ALS RESEARCH AND TREATMENT
CONFLICT OF INTEREST
COPYRIGHT AND PERMISSION STATEMENT
REFERENCES
Index
End User License Agreement
List of Tables
Chapter 1
TABLE 1.1 Spectrum of clinical disease phenotypes associated with genetic var...
Chapter 5
TABLE 5.1 Summary of key findings linking ALS and the microbiome.
Chapter 9
TABLE 9.1 Common adaptive trial designs.
List of Illustrations
Chapter 2
FIGURE 2.1 Timeline of ALS gene discovery and the rate of genetically explai...
Chapter 3
FIGURE 3.1 Risk factors in proposed etiologies for sALS. Susceptibility gene...
Chapter 4
FIGURE 4.1 People with lytico (ALS) and bodig (PDC) on Guam. (a) A woman bed...
FIGURE 4.2 (a) Decline by birth year in the numbers of newly diagnosed ALS, ...
FIGURE 4.3 Pedigrees of four typical, unrelated families of Umatac village i...
FIGURE 4.4 Cycad tree (
Cycas micronesica
K.D. Hill) on Guam.
FIGURE 4.5 Venn diagram showing suggested interactions of genes and toxicant...
Chapter 5
FIGURE 5.1 Main hypotheses explaining the role of the microbiome in ALS. The...
Chapter 6
FIGURE 6.1 Schematic of protein misfolding and aggregation process and the a...
Chapter 7
FIGURE 7.1 Schematic of the time course of how glial cells have been reporte...
Chapter 9
FIGURE 9.1 Platform trials allow the evaluation of multiple therapies under ...
FIGURE 9.2 Platform trials reduce the number of participants assigned to the...
Guide
Cover Page
Title Page
Copyright
Dedication
Contributors
Foreword
Preface
Acknowledgments
Table of Contents
Begin Reading
Index
WILEY END USER LICENSE AGREEMENT
Pages
iii
iv
v
xiii
xiv
xv
xvii
xviii
xix
xxi
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
201
202
203
204
205
206
207
208
209
210
211
212
213
Spectrums of Amyotrophic Lateral Sclerosis
Heterogeneity, Pathogenesis and Therapeutic Directions
EDITED BY
Christopher A. Shaw and Jessica R. Morrice
University of British Columbia, Canada
This edition first published 2021© 2021 John Wiley & Sons Ltd
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.
The right of Christopher A. Shaw and Jessica R. Morrice to be identified as the authors of the editorial material in this work has been asserted in accordance with law.
Registered OfficesJohn Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USAJohn Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK
Editorial Office9600 Garsington Road, Oxford, OX4 2DQ, UK
For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com.
Wiley also publishes its books in a variety of electronic formats and by print‐on‐demand. Some content that appears in standard print versions of this book may not be available in other formats.
Limit of Liability/Disclaimer of WarrantyWhile the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.
Library of Congress Cataloging‐in‐Publication Data
Names: Shaw, Christopher A. (Christopher Ariel), editor. | Morrice, Jessica R., editor.Title: Spectrums of amyotrophic lateral sclerosis : heterogeneity, Pathogenesis and therapeutic directions / edited by Christopher A. Shaw and Jessica R. Morrice.Description: Hoboken, NJ : Wiley-Blackwell, 2021. | Includes bibliographical references and index.Identifiers: LCCN 2021003406 (print) | LCCN 2021003407 (ebook) | ISBN 9781119745495 (hardback) | ISBN 9781119745501 (adobe pdf) | ISBN 9781119745518 (epub)Subjects: MESH: Amyotrophic Lateral Sclerosis–genetics | Amyotrophic Lateral Sclerosis–drug therapy | Genetic Heterogeneity | Spectrum Analysis | Models, GeneticClassification: LCC RC406.A24 (print) | LCC RC406.A24 (ebook) | NLM WE 552 | DDC 616.8/39–dc23LC record available at https://lccn.loc.gov/2021003406LC ebook record available at https://lccn.loc.gov/2021003407
Cover Design: WileyCover Image: © Emma McEachern
This book is dedicated to people living with ALS, their families, and those who care for them.
Contributors
Christen G. Chisholm, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, New South Wales, Australia; Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, New South Wales, Australia
Roger S. Chung, Motor Neuron Disease Research Centre, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia
Robert A. Déziel, CNS Contract Research Corp, Charlottetown, Prince Edward Island, Canada
Patrick A. Dion, Montreal Neurological Institute and Hospital, McGill University, Montréal, Québec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, Québec, Canada
Angela Genge, Montreal Neurological Institute and Hospital, Montréal, Québec, Canada
Daphne A. Gill, CNS Contract Research Corp, Charlottetown, Prince Edward Island, Canada; Department of Biomedical Sciences, University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada
Manuel Graeber, Brain Tumor Research Laboratories, Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia
Cheryl Y. Gregory‐Evans, Experimental Medicine Program, University of British Columbia, Vancouver, British Columbia, Canada; Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, British Columbia, Canada; Program in Neuroscience, University of British Columbia, Vancouver, British Columbia, Canada
Denis G. Kay, Alpha Cognition Inc., Charlottetown, Prince Edward Island, Canada
Charles Krieger, Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada; Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Division of Neurology, Vancouver Coastal Health, Vancouver, British Columbia, Canada
Michael Kuo, Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, British Columbia, Canada
Audrey Labarre, Department of Neuroscience, University of Montréal, Montréal, Québec, Canada; Centre de recherche du centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada
Serena Lattante, Unità Operativa Complessa di Genetica Medica, Dipartimento di Scienze di Laboratorio e Infettivologico, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Albert Lee, Motor Neuron Disease Research Centre, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia
Thomas E. Marler, College of Natural and Applied Sciences, University of Guam, Mangilao, Guam, USA
Amber L. Marriott, CNS Contract Research Corp, Charlottetown, Prince Edward Island, Canada
Luke McAlary, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, New South Wales, Australia; Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, New South Wales, Australia
Jessica R. Morrice, Experimental Medicine Program, University of British Columbia, Vancouver, British Columbia, Canada
Marco Morsch, Motor Neuron Disease Research Centre, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia
Alex Parker, Department of Neuroscience, University of Montréal, Montréal, Québec, Canada; Centre de recherche du centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada
Rowan A.W. Radford, Motor Neuron Disease Research Centre, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia
Jay P. Ross, Department of Human Genetics, McGill University, Montréal, Québec, Canada; Montréal Neurological Institute and Hospital, McGill University, Montréal, Québec, Canada
Guy A. Rouleau, Department of Human Genetics, McGill University, Montréal, Québec, Canada; Montreal Neurological Institute and Hospital, McGill University, Montréal, Québec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, Québec, Canada
Mario Sabatelli, Sezione di Medicina Genomica, Dipartimento Scienze della Vita e Sanità Pubblica, Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, Italy
Kristiana Salmon, Montreal Neurological Institute and Hospital, Montréal, Québec, Canada
Natalie M. Scherer, Motor Neuron Disease Research Centre, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia
Christopher A. Shaw, Experimental Medicine Program, University of British Columbia, Vancouver, British Columbia, Canada; Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, British Columbia, Canada; Department of Pathology, University of British Columbia, Vancouver, British Columbia, Canada; Program in Neuroscience, University of British Columbia, Vancouver, British Columbia, Canada
Ted Stehr, ALS Society of BC Director, and person living with ALS
Andres Vidal‐Itriago, Motor Neuron Disease Research Centre, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia
Justin J. Yerbury, Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, New South Wales, Australia; Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, New South Wales, Australia
Foreword
Charles Krieger
Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada
Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
Division of Neurology, Vancouver Coastal Health, Vancouver, British Columbia, Canada
The past decade or so has seen a substantial increase in the extent of research directly or indirectly related to amyotrophic lateral sclerosis (ALS). Unfortunately, this research has had limited impact on the clinical course of patients with ALS, suggesting that in many fundamental ways we do not really understand this disease. Numerous observations still defy a clear explanation. For instance, how is it that mutations in various genes, seemingly without a clear interaction in a signaling cascade or pathophysiologic mechanism, all result in a disease with a superficially similar phenotype, a phenotype that is shared with patients where no known gene mutations are present? How is it that the rate of progression of ALS is so rapid and unresponsive to modulation in some patients, yet a lucky few will have the disease course slow substantially? Why are there specific patterns of nervous system involvement in ALS such as “classic” ALS (Charcot type), bulbar ALS (perhaps better described by the original name of “glosso‐labio‐pharyngeal paralysis”), progressive muscular atrophy, and primary lateral sclerosis? What is the relation between the loss of motoneurons and their axons and the progressive decline in corticospinal and other descending connections? What is the basis of fasciculations? How does ALS “spread” so rapidly in the nervous system? These and other questions remain unanswered.
It is also interesting to look back at how our view of ALS research has changed over time. A clinician or scientist of 25 or 50 years ago would not have seen much investigation into ALS. To those of us who were involved with ALS at that time, the disease appeared neglected. Potentially, to a researcher investigating ALS 50 years ago, it also might have seemed that a treatment for this disease would be relatively straightforward, compared to the treatment of other neurological diseases like Alzheimer's disease or Parkinson's disease. ALS was characterized by the loss of neuronal populations that were well studied, even decades ago, and affected cells might be amenable to the delivery of intrathecal or intramuscular treatment to augment the health of dying neurons and so prolong patient survival.
How times have changed! Instead of being a neglected disorder, there has been considerable scientific and public interest in ALS, due not only to events like the Ice Bucket Challenge, but also to social media and increasing public awareness. Second, the initial hopes that the disease would turn out to be treatable and responsive to trophic molecules and other factors that would improve the “metabolism” of motoneurons have not yet borne fruit. In retrospect, it seems clear that given the complexity of motoneuron physiology, the difficulty of successful treatment may not have been fully appreciated. Furthermore, the scientific community generally has woken up to the challenge that ALS poses, and many labs around the world are investigating aspects of the disease: the genetics of ALS, the relation between viruses and ALS, RNA‐binding proteins, risk genes and environmental toxins, as well as other topics that are reviewed in the present volume.
We can only hope that this new volume will be a stimulus for continued research on ALS and result in insights into this enigmatic, frustrating, and tragic illness.
Preface
Source: Reproduced with the permission of Ted Stehr.
All humanity is on a train speeding through time. The name of the train is life. And like a train you might see in India, it's covered with people, inside and out. People inside are seated in different classes and are engaged in all manner of activities. The people on the roof would love to be inside. They are the sick. The wind buffets them, the rain drenches them, and the sun beats down on them. And each time the train jostles or turns, they have to quickly cling on to prevent them from sliding off and ending their journey.
The terminally ill cling precariously to the side of the train. They try to find perches on the thin window ledges or doorway openings. Some of them have ALS. They are exhausted from the relentless wind and weather, from standing, and from the strain of grasping whatever they can to keep from falling. Often the exhaustion is so great that they feel it might be easier to just let go. But something miraculous happens. People inside the train have given up their seats, walked over to the windows, and put arms around those desperate people. They say, “Don't worry, I have you. Relax for a while, and I'll hold on to you.”
Who are these kind people? They are like those from the ALS Clinic or the ALS Society or its donors. By vocation, by volunteering, or by donating, they give help to people who urgently need it.
ALS patients like me need much more than the love and support of their care givers and healthcare providers. We need hoists and slings to move us; specialized wheelchairs to help us to get around; and hospital beds for support, care, and comfort. As our needs grow more complex, the list gets longer and more expensive. But this equipment often makes the unbearable bearable. Some of it literally keeps us alive.
Please donate to the ALS Society of British Columbia. When you do, you are saying, “Hang on, fellow traveler: I see that you need help. Grab my arm.”
Typed on my eye gaze computer.
Ted Stehr
Acknowledgments
We thank Michael Kuo and Suresh Bairwa from our laboratory for their assistance. We also thank those at Wiley – Justin Jeffryes, Julia Squarr, Rosie Hayden, and Tom Marriott – for their guidance at all stages of the production of this book, and Tiffany Taylor for her hard work as the copy editor. Finally, we are grateful for contributor suggestions from David Taylor at ALS Canada.
CHAPTER 1Clinical Heterogeneity of ALS – Implications for Models and Therapeutic Development
Serena Lattante1,2 and Mario Sabatelli3,4
1 Unità Operativa Complessa di Genetica Medica, Dipartimento di Scienze di Laboratorio e Infettivologico, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
2 Sezione di Medicina Genomica, Dipartimento Scienze della Vita e Sanità Pubblica, Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, Italy
3 Centro Clinico NEMO adulti, U.O.C. Neurologia, Dipartimento di Scienze dell’Invecchiamento, Neurologiche, Ortopediche e della Testa‐Collo Fondazione
4 Sezione di Neurologia, Dipartimento di Neuroscienze, Facoltà di Medicina e Chirurgia, Università Cattolica Sacro Cuore, Rome, Italy
INTRODUCTION
Amyotrophic lateral sclerosis (ALS) was first described in 1874 as a specific neurological disease by the French neurologist Jean‐Martin Charcot, who chose this term to reflect both clinical observations and post‐mortem pathological findings. Amyotrophic refers to clinical evidence of muscle atrophy as a consequence of the loss of lower motor neurons (LMNs). Lateral sclerosis refers to the pathological observation of hardness of the lateral columns of the spinal cord, following upper motor neuron (UMN) degeneration [1]. UMN degeneration is followed by the formation of a sort of scar. The disease leads to progressive paralysis, with death occurring due to respiratory failure within three to five years after symptom onset.
The classical form is characterized by the concomitant involvement of UMNs in the cerebral cortex and LMNs located in the brainstem and the spinal cord. Clinical manifestations of UMN damage are loss of dexterity of the hands and spastic gait associated with overactive tendon reflexes. These signs are frequently associated with pathological reflexes, including Chaddock and Babinski signs (extension of the big toe after rubbing the lateral malleolus and the sole of the foot, respectively) and Hoffmann sign (flexion and adduction of index finger and thumb when flicking the nail of the middle finger downward). Corticobulbar involvement leads to slurred speech and difficulty swallowing, often with pathological crying and laughing. The consequence of LMN degeneration is weakness, which may involve any muscle of the body including those of the tongue, pharynx, or larynx (innervated by bulbar motor neurons); those of upper and lower limbs; and the respiratory muscles. Oculomotor and Onuf's motor neurons are usually spared. Muscular atrophy, reduced reflexes, and signs of hyperexcitability in motor neurons, such as fasciculation and cramps, are additional features of LMN degeneration.
The combination of the these symptoms and signs of UMN and LMN dysfunction results in a peculiar and stereotypical picture, which in most cases is easy for expert clinicians to identify. However, there is an evident clinical heterogeneity among ALS patients, which is determined by several independent elements. The age of onset and survival, two major phenotype features, show a marked variability among patients. Furthermore, the relative number of UMN and LMN signs may show substantial differences. An additional contributor to this heterogeneity is the evidence that the types of cells impaired in ALS may extend beyond UMNs and LMNs to include the frontal and temporal cortex, extrapyramidal system, peripheral nerves, and skeletal muscles, giving rise to variable and sometimes overlapping phenotypes.
Finally, genetic research has revealed that ALS is linked with several causative genes – a list that will probably increase in the coming years due to the rapid improvement of next‐generation sequencing technologies. ALS‐related genes are implicated in various cellular functions, including RNA metabolism, autophagy, and axonal transport, suggesting significant heterogeneity in disease mechanisms as well.
Thus, it appears that ALS is used as an umbrella term referring to a spectrum of disorders with diverse clinical manifestations, heterogeneous disease mechanisms, and (probably) different responses to therapies. On the other hand, all ALS patients, except carriers of superoxide dismutase 1 (SOD1) and fused in sarcoma (FUS) variants, appear to be unified by a single pathological signature: the presence of abnormal accumulation of the transactivation response DNA binding protein (TDP‐43) in the cytoplasm of neuronal and glial cells [2].
CLINICAL HETEROGENEITY OF ALS
Familial and Sporadic ALS
The disease occurs sporadically in the majority of cases (sporadic amyotrophic lateral sclerosis [sALS]), and nearly 10% of patients have a positive family history (familial amyotrophic lateral sclerosis [fALS]) [3]. However, the dichotomy between fALS and sALS is less clear than previously assumed, since several clinical, pathological, and genetic observations support the view that they are linked with each other over a continuum. From a clinical point of view, patients with sALS are indistinguishable from those with fALS. Both conditions show similar pathological patterns – the presence of ubiquitinated TDP‐43 positive inclusions in neuronal cells – with the only exception being patients with SOD1 and FUS mutations in which the SOD1 and FUS proteins are detected, respectively [4]. Importantly, fewer than 50% of fALS patients show a clear Mendelian inheritance, usually autosomal‐dominant (definite fALS). In the remaining fALS cases, the genetic architecture is less clear as familiarity is assumed by the presence of a single relative with ALS beyond the propositus. These cases are defined as probable fALS when the affected subject is a first‐ or second‐degree relative and possible fALS when the subject is more distant than second‐degree. Finally, the most consistent link between sALS and fALS is the observation that all genes involved in fALS are invariably found to be mutated in patients with apparently sporadic disease [3]. Genetic variants in major ALS genes have been detected in about 15% of sporadic forms [5, 6].
Age of Onset
ALS affects people of all ages, with a peak between ages 60 and 79. Recent population‐based studies reported a prevalence of ALS between 4.1 and 8.4 per 100 000 [7]. Patients with onset in the first two decades are extremely rare; such cases are termed juvenile ALS. This appears to be a different condition than classic ALS as it is familial in most cases, generally has autosomal recessive inheritance, and shows a very prolonged course. Patients with onset between 20 and 40 years are said to have young‐adult ALS; this is otherwise classic ALS, although it has peculiar clinical features including predominant UMN signs, male prevalence, and more prolonged survival (usually greater than five years). It remains unclear whether distinctive clinical features of young‐adult ALS are related to a different disease mechanism. Finally, very rare patients with onset before 20 years show an otherwise classic ALS with sporadic occurrence and an aggressive course. Most of the reported cases harbor a de novo mutation in the FUS gene.
Survival
The median survival of ALS is approximately three years from the onset, and about 70% of patients die within five years from onset. However, the duration of the disease differs widely in individual patients, ranging from a few months to over 10 years. Such remarkable variability is a major factor in favor of the hypothesis of ALS as a syndrome rather than a single disease. Median survival is worse in patients with bulbar onset ALS than with the spinal onset. Patients with disease onset before the age of 40 and patients with predominant UMN signs show a better prognosis. In most ALS patients, the cause of death is respiratory failure due to the degeneration of motor neurons controlling thoracic and diaphragmatic muscles. Of note, both the temporal and spatial patterns of the disease spread are important determinants of survival. Regarding the temporal pattern, the spreading rate of the degenerative process may vary among patients, with some patients showing a very rapid, aggressive course and others a slow progression. The spatial pattern is also important, since the sequence in which various body regions are involved is extremely variable and the survival changes if respiratory muscles are among the first or last to be affected.
Classic ALS, LMN Form, and UMN Form
By definition, ALS is characterized by a combination of LMN and UMN clinical and electrophysiological signs. However, the relative mix of UMN and LMN impairment is highly variable among patients, and clinical manifestations of ALS exist on a continuum whose extremes are represented by cases showing pure LMN dysfunction on one side and cases with pure UMN signs on the other side. Classic ALS (Charcot type) is the most frequent form, accounting for about 70–90% of cases, and is characterized by predominant LMN signs combined with slight to moderate pyramidal signs. Patients with pure LMN signs without any accompanying clinical or electrophysiological UMN signs are labeled as having progressive muscular atrophy (PMA) and represent about 5–10% of cases. However, the demonstration that UMN pathology is present at autopsy in 50% of PMA patients indicates that, in at least some cases, pyramidal signs are simply masked by LMN dysfunction on both clinical and electrophysiological grounds. For this reason, the presence of preserved but not hyperactive reflexes in atrophic limbs should be interpreted as UMN impairment. PMA and ALS are not distinct entities, as they show significant phenotypic and genetic overlap. About 2–5% of patients with motor neuron disease show a pure pyramidal form with predominant spino‐bulbar spasticity, known as primary lateral sclerosis (PLS). The onset of PLS is generally after 40 years, and the disease duration is significantly longer than in classic ALS. A small proportion of PLS patients develop a clear ALS phenotype, usually within three to four years from the onset, while others show only minimal LMN impairment; most cases remain PLS for decades. ALS patients with predominant pyramidal signs consisting mainly of severe spino‐bulbar spasticity are said to have upper motor neuron‐dominant amyotrophic lateral sclerosis (UMN‐D ALS). These signs are associated with slight LMN signs, usually in the hands. This phenotype is frequent in the young‐adult group and males, and it has a better prognosis than classic ALS [8–10].
Site of Onset
ALS begins focally at a seemingly random location and progresses to involve other body regions through anatomically connected pathways and/or neighboring regions. Approximately one‐fourth of patients show initial manifestations in the muscles innervated by motor neurons residing in the medulla (bulbar onset), one‐third in the upper limb muscles, and one‐third in the lower limb muscles whose motor neurons lie in the spinal cord (spinal onset). A small proportion of patients (2–5%) show respiratory symptoms at presentation. These cases are often difficult to diagnose because the absence of additional neurological signs can be misleading. The clinical phenotype at the onset, when temporal–spatial summation hasn't yet occurred, together with additional characteristics, may be important tools to delineate peculiar phenotypes, including spinal, bulbar, pseudopolyneuritic, emiparetic, and flail‐arm forms. It remains to be clarified if these clinical pictures correspond to distinct nosological entities or are the simple consequence of stochastic phenomena.
Bulbar ALS usually presents with dysarthria and dysphagia due to a variable combination of impairment of LMNs located in the IX, X, and XII nuclei and of the corticobulbar fibers. Bulbar symptoms and signs may be the only manifestation for several months before limb symptoms occur and when only corticobulbar signs are present, the diagnosis of ALS is frequently overlooked. Bulbar onset is more frequent in females and has a worse prognosis than the spinal onset form. In pseudopolyneuritic ALS (Patrikios' disease), weakness and atrophy start in distal limb muscles with frequent absence of tendon reflexes, thus mimicking a neuropathy [11]. The flail‐arm form (Vulpian‐Bernhart syndrome) is characterized by symmetric, predominantly proximal, wasting and weakness of both arms with relative sparing of lower limbs in the initial phases. This ALS form is prevalent in males, starts after the age of 40, and shows a slightly slower disease progression than classic ALS [12, 13].
Diagnosis of ALS
To date, there are no reliable diagnostic tests for ALS, and clinicians rely on the clinical evidence of a combination of UMNs and LMNs in the same body region, electromyographic confirmation of ongoing LMN degeneration, and the exclusion of mimicking conditions. Motor multifocal neuropathy, Kennedy disease, inclusion body myopathy, Sandoff disease, Morvan syndrome, paraneoplastic encephalomyelitis, inflammatory multineuropathies, and compressive myelopathies are conditions that may be confused with ALS and should be accurately evaluated. Criteria for the diagnosis of ALS have been established and are known as the El Escorial criteria, but they are more useful in the research field than in the clinical setting [14, 15].
ALS and Its Relationship with Frontotemporal Dementia and Myopathies
ALS has long been considered a paradigm of pure motor neuron disorder. However, genetic discoveries have shown that other cell types may be involved, linking ALS to other diseases. The most common and well‐established condition connected with ALS is frontotemporal dementia (FTD). Frontotemporal lobar degeneration (FTLD) consists of the degeneration of the frontal and temporal lobes of the brain, leading to atrophy, and occurs with an incidence of 3.5–4.1/100 000 per year in individuals under 65 [16, 17]. Clinically, this is the second most common cause of early‐onset dementia, referred to as FTD, and is familial in 20–30% of cases. Variants of FTLD have been described based on clinical signs. Behavioral variant frontotemporal dementia (bvFTD) is the most frequent form and is characterized by behavioral problems – apathy and disinhibition – and a decline in executive functions. Progressive nonfluent aphasia (PNFA) is characterized by language problems including nonfluent speech, dysarthria, poor articulation, and agrammatism with preserved comprehension. The third variant is semantic dementia (SD), also called progressive fluent aphasia (PFA), characterized by the loss of semantic and conceptual knowledge. All these FTLD variants have been described in patients with ALS.
Insoluble proteins aggregate in the neurons of patients with FTLD, leading to three different pathological variants: FTLD‐Tau, characterized by the accumulation of the microtubule‐associated protein and often by mutations in the gene encoding for the same protein (MAPT) (~30–40% of cases) [18]; FTLD‐FUS, containing the FUS sarcoma protein (~10% of cases) [19]; and the most frequent, FTLD‐TDP, with TDP‐43 aggregates (~50–60% of cases) [18–21].
From a clinical point of view, FTD and ALS overlap since 15–18% of ALS patients have FTD and 15% of FTD patients show motor dysfunctions [22, 23]. ALS and FTD also share genetic and neuropathological features, thus leading to the definition of the ALS/FTD spectrum where ALS and FTD are the extremes of a continuum. From a genetic point of view, this idea has been consolidated by the identification of the gene C9orf72 [24, 25], whose pathogenic expansion has been described in 30–50% of fALS, 25% of familial FTD, 5–7% of sALS, and 6% of sporadic FTD cases in different populations [26, 27]. Furthermore, other genes have been associated with the ALS/FTD spectrum: TBK1, TARDBP, FUS, and SQSTM1[28]. Finally, with regard to neuropathology, TDP‐43 inclusions in neuronal cells are a hallmark of ALS as well as of a proportion of FTD.
Recent genetic evidence, along with clinical and pathological observations, indicate that ALS may be linked to primary muscle disorders as well. Mutations in valosin‐containing protein (VCP), previously identified in a proportion of patients with hereditary inclusion‐body myopathy (IBM), were later detected in a subset of sALS and fALS cases [29]. Additional genes, including MATR3, hnRNPA1, hnRNPA2B1, and SQSTM1, have been identified, which are responsible for an ALS/myopathy spectrum with overlapping phenotypes [30–32]. Interestingly, most myopathies associated with ALS are distal myopathies with evidence of rimmed vacuoles at muscle biopsy. These structures represent the accumulation of autophagic vacuoles due to lysosomal dysfunction or protein accumulation.
Paget's disease of the bone, extrapyramidal syndromes, psychiatric disorders, and peripheral neuropathies are additional conditions that are mechanistically linked to ALS. The spectrum of clinical phenotypes associated with major ALS‐associated genes is listed in Table 1.1 [24, 25, 29, 30,32–66].
PLEIOTROPY OF ALS GENES
SOD1 is the only ALS‐associated gene that has been associated exclusively with an isolated motor phenotype. A common phenomenon for all other ALS genes is pleiotropy, which means a genetic variant can be associated with multiple phenotypic traits. The same genetic variant can cause not only different ALS subtypes in families, in terms of age of onset and disease course, but also different diseases. Examples of pleiotropic genes are C9orf72 and VCP. In the same family, C9orf72 carriers can have only ALS, only FTD, or overlapping ALS/FTD phenotypes. Furthermore, the same pathogenic variant in VCP has been detected in patients with ALS, FTD, IBM, and Charcot‐Marie‐Tooth type 2 (CMT2) [67]. The opposite is also true: different pathogenic variants in the same ALS‐associated gene can cause an identical phenotype.
TABLE 1.1 Spectrum of clinical disease phenotypes associated with genetic variants.
ALS
FTD
Myopathy
Parkinson's disease
Paget's disease
Others
SOD1
+
44
–
–
–
–
–
C9orf72
+
24,25
+
24,25
–
+
45
+/−
46
Psychiatric disorders
[33]
, Huntington disease
[34]
TARDBP
+
47,48
+
49
–
+
50
–
–
FUS
+
51,52
+
53
–
–
–
Hereditary essential tremor 4
[35]
NEK1
+
54
–
–
–
–
Short‐rib thoracic dysplasia
[36]
TBK1
+
55
+
56
–
–
–
Herpes simplex encephalitis
[37]
MATR3
+
32
+
32
+
57
–
–
–
VCP
+
29
+
58
+
58
–
+
58
Charcot‐Marie‐Tooth type 2
[38]
SQSTM1
+
30
+
59
+
60
–
+
61
Childhood‐onset neurodegeneration with ataxia, dystonia, and gaze palsy
[39]
OPTN
+
62
+
63
–
+
64
+
65
Open angle glaucoma
[40]
KIF5A
+
66
–
–
–
–
Hereditary spastic paraplegia
[41]
, Charcot‐Marie‐Tooth type 2
[42]
, neonatal intractable myoclonus
[43]
Presence (+) or absence (−) of clinical signs in patients with variants in different genes is reported in the table.
High‐throughput sequencing studies have shown that a consistent number of patients with the C9orf72 expansion have additional variants in other ALS‐associated genes, suggesting that pleiotropy can be explained by an oligogenic model [5, 27,68–70].
With rare exceptions, it is not possible to establish a genotype–phenotype correlation in ALS. The variants p.D11Y, p.D90A, and p.G93D in SOD1 are associated with a relatively benign form of motor neuron disease with distal limb distribution [71–74], while p.A4V and p.G85S are associated with a rapid course [75, 76]. Some mutations in FUS, including p.P525L and frameshift mutations, are frequently associated with juvenile‐onset ALS with an aggressive course [77–79].
GENETIC MODELS TO STUDY ALS
In Vivo Models
ALS is currently untreatable. Riluzole and edaravone, the two drugs approved by the US Food and Drug Administration (FDA), increase survival by a few months, blocking excessive glutamatergic neurotransmission and preventing oxidative stress damage, respectively, but they are not able to halt or cure the disease [80]. Genetic models represent a very useful tool to identify the concrete target of new drugs. Of course, no model can fully reproduce the human condition, especially its clinical heterogeneity, but a combination of in vitro and in vivo models can help to investigate the mechanisms underlying the disease and explore epistatic interactions. Since the first genetic discoveries, molecular biology techniques have made it possible to insert gene mutations and express mutant proteins in a number of animal models (see details in Chapter 8). Small animals such as Drosophila melanogaster and Danio rerio (zebrafish), have been widely used due to the simplicity and rapidity of manipulations, especially for drug screening. The zebrafish has many advantages in this sense, mostly because it is a vertebrate and has high genetic homology with humans. The zebrafish can be used at the embryonic stage, taking advantage of egg transparency and its rapid development, which can be followed in real time; and also at the adult stage, using transgenic lines. Motor phenotypes can be easily detected and analyzed, and in vivo imaging can be promptly performed. Genetic interactions can be tested as well as mechanisms of action of pathogenesis. High‐throughput drug screening can be done to test libraries containing thousands of chemical compounds at the same time. Since the zebrafish is not a mammal and does not have UMNs (the corticospinal and rubrospinal tracts are absent), it can be considered a very useful tool to study cellular dynamics in vivo and may be used prior to other models, such as rodents [81, 82].
A wide range of murine models has been created [83] but the most commonly used remains the first one developed: a transgenic strain carrying the SOD1G93A pathogenic variant [84]. This model has been used to test most drugs in preclinical phases. It should be noted that these treatments are administrated at the pre‐symptomatic stage, whereas ALS patients are treated after a disease onset that seems to be preceded by a long pre‐symptomatic period. To better investigate the pre‐symptomatic stage, a SOD1 pig model has recently been obtained [85]. Since pigs have a long lifespan, transgenic pigs, stably expressing the human pathological allele SOD1G93A, have a pre‐symptomatic phase of about 27 months. After this period, gait abnormality and concomitant dysphagia appear and progress rapidly with severe respiratory impairment. SOD1 animal models have been used in preclinical investigations of almost all drugs used in clinical trials. However, the principal limit of this model is that TDP‐43 pathology, which is present in about 97% of all ALS subtypes, is not detected in SOD1mutated patients, suggesting different disease mechanisms. In addition, preclinical studies performed in mice have failed to be transferred to humans [86].
Considerable efforts have been undertaken to study the biological role of C9orf72, because its pathogenic expansion is the most frequent cause of ALS and FTD in populations of European descent. Drosophila, zebrafish, and rodents have been used to test various hypotheses of the C9orf72 mechanism, including loss of function, leading to haploinsufficiency of the gene, and gain of function, with the accumulation of RNA foci and dipeptide repeats (DPR) resulting from non‐conventional repeat translation. TDP‐43 inclusions are detectable in mice expressing the C9orf72 expanded allele, suggesting that TDP‐43 is downstream of C9orf72. Knockout mice show an inflammatory phenotype, thus implicating C9orf72 in immune regulation and the autophagic pathway [87]. Mice expressing the repeat expansion present with RNA foci and DPR, but they do not have a behavioral phenotype, suggesting that the gain of function is not sufficient to cause the disease [88, 89]. A combination of different mechanisms is probably required for disease development [90].
Different animal models, reproducing mutations in different genes, are needed to investigate ALS in its complexity along with the clinical overlap with other diseases of the spectrum. For example, a transgenic mouse has recently been described, carrying the MATR3S85C variant. This model shows myopathic histological changes: TDP‐43 aggregates in muscles, and respiratory problems occur due to myopathic changes in diaphragm muscles. Interestingly, the observed myotoxicity recapitulates the clinicopathological features of distal myopathy and ALS [91]. Also, a TBK1 mouse, recently developed, reproduces the main symptoms of ALS/FTD. Mice carrying the conditional neuronal deletion of TBK1 show memory deficits and reduced locomotor activity. Interestingly, TBK1 overexpression extended the lifespan of symptomatic mice not only for TBK1 knockout strains but also for SOD1G93A mice, thus suggesting that TBK1 and SOD1 are probably part of the same pathway and can be targeted by the same drugs [92].
By comparing phenotypes across ALS models carrying mutations in different genes, it is possible to study the disease as broadly as possible.
In Vitro Models
The combination of in vivo and in vitro models can be a good strategy to investigate disease mechanisms in depth. In recent years, a number of studies have been performed on commercial cells engineered to carry mutations in ALS‐associated genes. In recent years, the innovative possibility of reprogramming somatic cells obtained from patients opened new avenues for ALS research. Hopefully it will lead to significant improvements in the future of regenerative medicine. Generating cells from patients has two significant advantages that are unique in this model:
It is possible to obtain human motor neurons, glial cells, and microglia, the cell types that are primarily affected by the disease and that have been studied in the past only as post‐mortem samples.
Cells obtained from patients carry exactly the same genetic background as the patient. This means there is no need to insert the genetic mutation artificially: it is possible to study cells as they are in nature. In this context, it is possible to investigate the disease mechanism in all ALS subtypes, including those with known and unknown genetic defects. Moreover, a genetic mutation that arises spontaneously can be corrected using gene‐editing techniques to revert the phenotype.
Two different strategies have been set up to reprogram cells from patients. The most commonly used is the generation of induced pluripotent stem cells (iPSCs) from skin fibroblasts [93] and their subsequent differentiation into motor neurons. The second strategy is the direct conversion of skin fibroblasts into motor neurons or glial cells [94].
Fibroblasts can be easily obtained through a skin biopsy, which is not invasive and is very well tolerated by patients. Specific transcription factors (Oct3/4, Sox2, Klf4, and c‐Myc) can be introduced by retroviral transduction into somatic cells to convert them into iPSCs [93]. To avoid side effects caused by the use of retroviruses that integrate in the genome, various tools have been developed, such as non‐integrating virus and mRNA transcription factors. The iPSCs have the ability to self‐renew in culture and can differentiate into cell types of all three germ layers while maintaining the patient's genetic background. Direct conversion of neuronal cells from fibroblasts allows us to bypass the pluripotent stage and can be obtained by overexpressing a combination of transcription factors [94]. Thanks to this strategy, the maturity of the cell, as well as its epigenetic signatures, are preserved; and stem cells can be a better method to study late‐onset diseases.
Once obtained, iPSCs can be differentiated into every kind of cell. The most recent innovative approach consists of generating three‐dimensional cell cultures called organoids, with the aim of better reproducing intercellular interactions and physiological properties. Organoids are particularly useful for drug testing since they better mimic patient's response and tolerability.
CONCLUSION
Recent genetic discoveries and progress in neuropathology have completely changed the perspective on ALS. The current idea is that ALS cannot be considered a single entity (as it was until a few years ago) but rather is part of a clinical spectrum of disease. Various clinical manifestations can be described depending on familial history, age of onset, site of onset, disease duration, and overlap with other conditions as cognitive impairment or myopathies. Animal and cellular models have been established to better characterize the disease pathogenesis and to link the disease to different biological pathways. All these models have the same goal: looking for treatments that can stop or at least significantly slow the disease progression.
CONFLICT OF INTEREST
The authors declare no potential conflict of interest with respect to research, authorship, and/or publication of this manuscript.
COPYRIGHT AND PERMISSION STATEMENT
To the best of our knowledge, the materials included in this chapter do not violate copyright laws. All original sources have been appropriately acknowledged and/or referenced. Where relevant, appropriate permissions have been obtained from the original copyright holder.
REFERENCES
1.
Rowland, L.P. and Shneider, N.A. (2001). Amyotrophic lateral sclerosis.
N Engl J Med
344 (22): 1688–1700.
2.
Neumann, M., Sampathu, D.M., Kwong, L.K. et al. (2006). Ubiquitinated TDP‐43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
Science
314 (5796): 130–133.
3.
Byrne, S., Bede, P., Elamin, M. et al. (2011). Proposed criteria for familial amyotrophic lateral sclerosis.
Amyotroph Lateral Scler
12 (3): 157–159.
4.
Saberi, S., Stauffer, J.E., Schulte, D.J., and Ravits, J. (2015). Neuropathology of amyotrophic lateral sclerosis and its variants.
Neurol Clin
33 (4): 855–876.
5.
Lattante, S., Conte, A., Zollino, M. et al. (2012). Contribution of major amyotrophic lateral sclerosis genes to the etiology of sporadic disease.
Neurology
79 (1): 66–72.
6.
Renton, A.E., Chiò, A., and Traynor, B.J. (2014). State of play in amyotrophic lateral sclerosis genetics.
Nat Neurosci
17 (1): 17–23.
7.
Longinetti, E. and Fang, F. (2019). Epidemiology of amyotrophic lateral sclerosis: an update of recent literature.
Curr Opin Neurol
32 (5): 771–776.
8.
Sabatelli, M., Madia, F., Conte, A. et al. (2008). Natural history of young‐adult amyotrophic lateral sclerosis.
Neurology
71 (12): 876–881.
9.
Sabatelli, M., Zollino, M., Luigetti, M. et al. (2011). Uncovering amyotrophic lateral sclerosis phenotypes: clinical features and long‐term follow‐up of upper motor neuron‐dominant ALS.
Amyotroph Lateral Scler
12 (4): 278–282.
10.
Swinnen, B. and Robberecht, W. (2014). The phenotypic variability of amyotrophic lateral sclerosis.
Nat Rev Neurol
10 (11): 661–670.
11.
Cappellari, A., Ciammola, A., and Silani, V. (2008). The pseudopolyneuritic form of amyotrophic lateral sclerosis (Patrikios' disease).
Electromyogr Clin Neurophysiol
48 (2): 75–81.
12.
Hu, M.T., Ellis, C.M., Al‐Chalabi, A. et al. (1998). Flail arm syndrome: a distinctive variant of amyotrophic lateral sclerosis.
J Neurol Neurosurg Psychiatry
65 (6): 950–951.
13.
Gamez, J., Cervera, C., and Codina, A. (1999). Flail arm syndrome of Vulpian‐Bernhart's form of amyotrophic lateral sclerosis.
J Neurol Neurosurg Psychiatry
67 (2): 258.
14.
Ludolph, A., Drory, V., Hardiman, O. et al. (2015). A revision of the El Escorial criteria −2015.
Amyotroph Lateral Scler Frontotemporal Degener
16 (5–6): 291–292.
15.
Agosta, F., Al‐Chalabi, A., Filippi, M. et al. (2015). The El Escorial criteria: strengths and weaknesses.
Amyotroph Lateral Scler Frontotemporal Degener
16 (1–2): 1–7.
16.
Ratnavalli, E., Brayne, C., Dawson, K., and Hodges, J.R. (2002). The prevalence of frontotemporal dementia.
Neurology
58 (11): 1615–1621.
17.
Harvey, R.J., Skelton‐Robinson, M., and Rossor, M.N. (2003). The prevalence and causes of dementia in people under the age of 65 years.
J Neurol Neurosurg Psychiatry
74 (9): 1206–1209.
18.
Mackenzie, I.R., Neumann, M., Bigio, E.H. et al. (2010). Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update.
Acta Neuropathol
119 (1): 1–4.
19.
Neumann, M., Roeber, S., Kretzschmar, H.A. et al. (2009). Abundant FUS‐immunoreactive pathology in neuronal intermediate filament inclusion disease.
Acta Neuropathol
118 (5): 605–616.
20.
Mackenzie, I.R., Neumann, M., Baborie, A. et al. (2011). A harmonized classification system for FTLD‐TDP pathology.
Acta Neuropathol
122 (1): 111–113.
21.
Mackenzie, I.R., Rademakers, R., and Neumann, M. (2010). TDP‐43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia.
Lancet Neurol
9 (10): 995–1007.
22.
Burrell, J.R., Kiernan, M.C., Vucic, S., and Hodges, J.R. (2011). Motor neuron dysfunction in frontotemporal dementia.
Brain
134 (Pt 9): 2582–2594.
23.
Lomen‐Hoerth, C., Anderson, T., and Miller, B. (2002). The overlap of amyotrophic lateral sclerosis and frontotemporal dementia.
Neurology
59 (7): 1077–1079.
24.
DeJesus‐Hernandez, M., Mackenzie, I.R., Boeve, B.F. et al. (2011). Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p‐linked FTD and ALS.
Neuron
72 (2): 245–256.
25.
Renton, A.E., Majounie, E., Waite, A. et al. (2011). A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21‐linked ALS‐FTD.
Neuron
72 (2): 257–268.
26.
Majounie, E., Renton, A.E., Mok, K. et al. (2012). Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross‐sectional study.
Lancet Neurol
11 (4): 323–330.
27.
van der Zee, J., Gijselinck, I., Dillen, L. et al. (2013). A pan‐European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and intermediate repeats.
Hum Mutat
34 (2): 363–373.
28.
Nguyen, H.P., Van Broeckhoven, C., and van der Zee, J. (2018). ALS genes in the genomic era and their implications for FTD.
Trends Genet
34 (6): 404–423.
29.
Johnson, J.O., Mandrioli, J., Benatar, M. et al. (2010). Exome sequencing reveals VCP mutations as a cause of familial ALS.
Neuron
68 (5): 857–864.
30.
Fecto, F., Yan, J., Vemula, S.P. et al. (2011). SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis.
Arch Neurol
68 (11): 1440–1446.
31.
Kim, H.J., Kim, N.C., Wang, Y.D. et al. (2013). Mutations in prion‐like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS.
Nature
495 (7442): 467–473.
32.
Johnson, J.O., Pioro, E.P., Boehringer, A. et al. (2014). Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis.
Nat Neurosci
17 (5): 664–666.
33.
Arighi, A., Fumagalli, G.G., Jacini, F. et al. (2012). Early onset behavioral variant frontotemporal dementia due to the C9ORF72 hexanucleotide repeat expansion: psychiatric clinical presentations.
J Alzheimers Dis
31 (2): 447–452.
34.
Beck, J., Poulter, M., Hensman, D. et al. (2013). Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population.
Am J Hum Genet
92 (3): 345–353.
35.
Merner, N.D., Girard, S.L., Catoire, H. et al. (2012). Exome sequencing identifies FUS mutations as a cause of essential tremor.
Am J Hum Genet
91 (2): 313–319.
36.
Thiel, C., Kessler, K., Giessl, A. et al. (2011). NEK1 mutations cause short‐rib polydactyly syndrome type majewski.
Am J Hum Genet
88 (1): 106–114.
37.
Herman, M., Ciancanelli, M., Ou, Y.H. et al. (2012). Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood.
J Exp Med
209 (9): 1567–1582.
38.
Gonzalez, M.A., Feely, S.M., Speziani, F. et al. (2014). A novel mutation in VCP causes charcot‐marie‐tooth type 2 disease.
Brain
137 (Pt 11): 2897–2902.
39.
Haack, T.B., Ignatius, E., Calvo‐Garrido, J. et al. (2016). Absence of the autophagy adaptor SQSTM1/p62 causes childhood‐onset neurodegeneration with ataxia, dystonia, and gaze palsy.
Am J Hum Genet
99 (3): 735–743.
40.
Rezaie, T., Child, A., Hitchings, R. et al. (2002). Adult‐onset primary open‐angle glaucoma caused by mutations in optineurin.
Science
295 (5557): 1077–1079.
41.
Reid, E., Kloos, M., Ashley‐Koch, A. et al. (2002). A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10).
Am J Hum Genet
71 (5): 1189–1194.
42.
Crimella, C., Baschirotto, C., Arnoldi, A. et al. (2012). Mutations in the motor and stalk domains of KIF5A in spastic paraplegia type 10 and in axonal charcot‐marie‐tooth type 2.
Clin Genet
82 (2): 157–164.
43.
Duis, J., Dean, S., Applegate, C. et al. (2016). KIF5A mutations cause an infantile onset phenotype including severe myoclonus with evidence of mitochondrial dysfunction.
Ann Neurol
80 (4): 633–637.
44.
Rosen, D.R., Siddique, T., Patterson, D. et al. (1993). Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis.
Nature
362 (6415): 59–62.
45.
Xi, Z., Zinman, L., Grinberg, Y. et al. (2012). Investigation of c9orf72 in 4 neurodegenerative disorders.
Arch Neurol
69 (12): 1583–1590.
46.
Rubino, E., Di Stefano, M., Galimberti, D. et al. (2020). C9ORF72 hexanucleotide repeat expansion frequency in patients with Paget's disease of bone.
Neurobiol Aging
85: 154.e1–154.e3.
47.
Kabashi, E., Valdmanis, P.N., Dion, P. et al. (2008). TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis.
Nat Genet
40 (5): 572–574.
48.
Sreedharan, J., Blair, I.P., Tripathi, V.B. et al. (2008). TDP‐43 mutations in familial and sporadic amyotrophic lateral sclerosis.
Science
319 (5870): 1668–1672.
49.
Kovacs, G.G., Murrell, J.R., Horvath, S. et al. (2009). TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea.
Mov Disord
24 (12): 1843–1847.
https://doi.org/10.1002/mds.22697
.
50.
Quadri, M., Cossu, G., Saddi, V. et al. (2011). Broadening the phenotype of TARDBP mutations: the TARDBP Ala382Thr mutation and Parkinson's disease in Sardinia.
Neurogenetics
12 (3): 203–209.
51.
