(Original PDF) Neurogenetics Part I

(Handbook of Clinical Neurology)

Go to download the full and correct content document:
https://ebooksecure.com/product/original-pdf-neurogenetics-part-i-handbook-of-clinica
l-neurology/
More products digital (pdf, epub, mobi) instant
download maybe you interests ...

(Original PDF) Neurogenetics, Part II (Handbook of

Clinical Neurology)

http://ebooksecure.com/product/original-pdf-neurogenetics-part-
ii-handbook-of-clinical-neurology/

Neuroimaging, Part I (Volume 135) (Handbook of Clinical

Neurology, Volume 135) 1st Edition - eBook PDF

https://ebooksecure.com/download/neuroimaging-part-i-ebook-pdf/

(eBook PDF) Translational Medicine in CNS Drug

Development, Volume 29

http://ebooksecure.com/product/ebook-pdf-translational-medicine-
in-cns-drug-development-volume-29/

Progress in Heterocyclic Chemistry Volume 29 1st

Edition - eBook PDF

https://ebooksecure.com/download/progress-in-heterocyclic-
chemistry-ebook-pdf/
Critical Care Neurology Part I 1st Edition Edition
Eelco F.M. Wijdicks And Andreas H. Kramer (Eds.) -
eBook PDF

https://ebooksecure.com/download/critical-care-neurology-part-i-
ebook-pdf/

Netter Atlas of Human Anatomy-Classic Regional

Approach, 8e (Mar 29, 2022)_(0323793738)_(Elsevier) NOT
TRUE PDF 8th Edition - eBook PDF

https://ebooksecure.com/download/netter-atlas-of-human-anatomy-
classic-regional-approach-8e-mar-29-2022_0323793738_elsevier-not-
true-pdf-ebook-pdf/

Cardiology-An Integrated Approach (Human Organ Systems)

(Dec 29, 2017)_(007179154X)_(McGraw-Hill) 1st Edition
Elmoselhi - eBook PDF

https://ebooksecure.com/download/cardiology-an-integrated-
approach-human-organ-systems-dec-29-2017_007179154x_mcgraw-hill-
ebook-pdf/

Kaufman’s Clinical Neurology for Psychiatrists - eBook

PDF

https://ebooksecure.com/download/kaufmans-clinical-neurology-for-
psychiatrists-ebook-pdf-2/

Clinical Neurology 10th Edition Roger P. Simon - eBook

PDF

https://ebooksecure.com/download/clinical-neurology-ebook-pdf/
 Foreword

These two volumes (147 and 148) on neurogenetics in the Handbook of Clinical Neurology series illustrate the enor-
mous impact that this discipline has had in the last few decades on understanding the variation that makes each of us
unique, on the diagnosis of neuropsychiatric disorders, and certainly also on basic neurobiology.
The “genetics revolution” started in 1953, when Watson and Crick published the elegant structure of our genetic
code. In 1990, Watson was appointed head of the Human Genome Project at the National Institutes of Health. Ten years
later, US President Bill Clinton announced that the first draft of the human genome was complete.
There is no doubt that the sequencing of the human genome has been a critical scientific milestone that has not only
changed the landscape of gene discovery tremendously but has also transformed our understanding of mechanisms
mediating the development, aging, and disorders of the brain. Likewise, new genetic methods, bioinformatics,
and genomic databases, which are discussed in Volume 147, have brought deeper insights into the subtle
complexities of the genetic architecture that determines plasticity and resilience of the developing and adult brain
and the risks of developing neuropsychiatric disorders.
Today, molecular genetic and genomic tests can provide a definitive diagnosis for many neurologic and psychiatric
disorders, as shown extensively in these two volumes, but they also bring new complex ethical issues. The nature-
versus-nurture discussion regarding the cause of neuropsychiatric disorders has taken on a new dimension with the
finding that environmental factors can epigenetically modulate the function of genes and influence disease
processes. The importance of animal models is discussed in various chapters, as is the major challenge for the field,
namely to bridge the gap between genes and neurotherapy.
We were very fortunate to have as volume editors three distinguished scholars: Daniel H. Geschwind of the David
Geffen School of Medicine at UCLA, Henry L. Paulson of the University of Michigan, and Christine Klein of the
Institute of Neurogenetics at the University of L€ubeck. They have assembled an excellent international and multidis-
ciplinary group of experts and guided them to create this comprehensive book. We are very grateful to them and to all
the contributors.
As always, it is a pleasure to thank Elsevier, our publisher—and in particular Michael Parkinson in Scotland,
and Mara Conner, Nikki Levy, and Kristi Anderson in San Diego—for their unfailing and expert assistance in the devel-
opment and production of this volume.
Michael J. Aminoff
François Boller
Dick F. Swaab
This page intentionally left blank
 Preface

We are grateful for the opportunity to edit these two neurogenetics volumes in the Handbook of Clinical Neurology
series. Since the publication of the Neurogenetics Directory as part of the series more than three decades ago, extraor-
dinary advances have occurred in understanding the pathophysiology of neurologic disorders, many of them fueled by
genetics and genomics. Prior to the early 1990s, gene hunting in neurogenetics was complicated by the lack of a human
genome roadmap. With the exception of metabolic disorders and chromosomal anomalies, few, if any, mutations caus-
ing rare Mendelian neurologic disorders or genetic variants contributing to the risk of developing common disorders
were known. Once a first-generation genome map was in hand, improvements in technology and statistical methods
and the development of large-scale collaborative studies created extraordinary momentum that continues to propel
genetic discoveries. Starting with identification of rare mutations causing neurodegenerative syndromes, such as spinal
bulbar muscular atrophy, Huntington disease, and ataxias, which were caused by triplet repeat expansions, the field has
progressed through linkage analysis and identification of mutations causing rare Mendelian forms of Alzheimer disease
or neurodevelopmental disorders, to identifying risk variants for more common disorders, such as migraine, multiple
sclerosis, autism spectrum disorder, and Alzheimer disease using genomewide association studies. These studies have
moved neurology beyond a gold standard consisting of pathologic descriptions of disease in postmortem tissues from
the central and peripheral nervous systems towards defining the root causes of disease, providing an unprecedented
opportunity to interrupt the mechanistic chains of events that underlie disease susceptibility. The 53 chapters in these
two neurogenetics volumes represent the frontier of neurogenetics and have been chosen to embody this promise.
The first eight chapters introduce basic concepts in genetics and genomics, ranging from epigenetics and bioinfor-
matics, to genetic testing in clinical practice, and to ethical issues. Progress has been so remarkable that a number of
these chapters could not even have been conceived of 30 years ago. Next we highlight some recurring themes, such as
triplet repeats, mitochondrial disorders, and polyglutamine disorders. Following this, the sections cover disease entities
such as movement disorders, neurodevelopmental disorders, dementias, paroxysmal disorders, neuromuscular disor-
ders, diseases of white matter and demyelination, cerebrovascular disorders, major adult psychiatric disorders (addic-
tion and obsessive compulsive disorder), and cancer and phakomatoses.
Since genetic factors influence virtually every neurologic condition, we have chosen to include a broad range of
topics, to emphasize key themes that are emerging in neurogenetics. Technology is an obvious driver, and changes
such as the advent of whole-exome sequencing (WES) as a clinical test make discovery of new genetic causes of disease
a part of everyday clinical diagnostics. Another theme is the overlap between neurology and psychiatry, where we hope
that coverage of certain representative psychiatric disorders illustrates the progress and the challenges in this field. In
some cases, genetics is actually changing diagnostic boundaries, leading to questions about pathology, which in many
cases has been considered the gold standard of definitive clinical diagnosis. One striking example is Friedreich ataxia,
originally defined as a disorder of early childhood, where more mild, adult-onset cases are now frequently identified
through genetic testing. Similarly, in Parkinson disease, patients with several genetic forms that cause classic clinical
parkinsonism may lack synuclein deposition, challenging the gold-standard pathologic diagnosis. In other conditions,
genetic progress has led to animal and cell models, which provide promise for mechanistic understanding. With this
wealth of advances come substantial challenges, most prominently in the largely unexplored territory of connecting
genetic variation through multiple levels of function, ranging from changes in chromatin, RNA expression, and protein
modifications, to cell biologic and network physiologic function and behavior. On a purely genetic level, the ability to
obtain whole-genome sequences (WGS) from substantial patient cohorts presents the challenge of interpreting the vast
amount of noncoding sequence queried by this approach, but whose function is largely unknown.
Now we live in an era when progress in creating truly high-performance computing and developments in technology
promise a US$100 genome, perhaps within the next 5 years. Notwithstanding the enormous bioinformatic and com-
putational challenges and costs, this means that the majority of patients are likely to have genetic information included
x PREFACE
as part of their medical record within the next decade. WES and WGS are coming into clinical practice: the diagnostic
rate for WES in undiagnosed disorders can be as high as 50% in certain cardiac condtions, averages around 30% for
most childhood neurologic disorders, including autism spectrum disorder, and is more than 20% for patients with a
wide range of sporadic ataxias but lacking a family history. Even at the lower end of the diagnostic rate, WES is
the most powerful single diagnostic test available for a wide range of previously undiagnosed disorders (see Chapter 2),
and genetic testing is increasingly replacing other diagnostic laboratory tests in several areas of neurology. Similarly,
genetic association studies have yielded multiple new directions in common diseases such as Alzheimer disease and
multiple sclerosis. It is clear that power in such studies is related to numbers, and that as we approach large enough
sample sizes, we will be able to understand the majority of common and rare genetic risks for all neurologic disorders.
So, we expect that soon we will know over 50% of the population risk for most common neurologic and psychiatric
disorders, and will base genetic-driven treatments for certain conditions on this knowledge. Such advances will give
rise to genetically driven precision healthcare, where diagnosis, prevention, prognosis, and treatment are tailored to the
individual patient. In parallel with advances in clinical oncology, we have reached the exciting stage of pioneering
genetic cause-directed molecular therapies for Duchenne muscular dystrophy and spinal muscular atrophy type 1.
Lastly, the degree and the precision of genetic and genomic data currently exceed that of systematically collected
(and quality-controlled) phenotypic information, which constitutes an increasingly important knowledge gap if we
are to effectively exploit all of the available (and newly generated) genetic data and use it to predict clinical outcomes.
In this regard, our current electronic health records will likely not be sufficient, and new, high-throughput methods of
phenotypic data collection and analysis will be needed.
Daniel H. Geschwind
Henry L. Paulson
Christine Klein
 Contributors
T. Bardakjian
Neurogenetics Program, Department of Neurology,
University of Pennsylvania, Philadelphia, PA,
United States
E. Berry-Kravis
Department of Neurological Sciences and Department of
Pediatrics; Biochemistry, Rush University, Chicago, IL,
United States
T.D. Bird
Department of Neurology, University of Washington and
Geriatric Research Center, VA Medical Center, Seattle,
WA, United States
J.R. Bishop
Department of Experimental and Clinical Pharmacology,
University of Minnesota, Minneapolis, MN, United
States
J. Chen
Interdepartmental Program in Bioinformatics and Semel
Institute for Neuroscience and Human Behavior,
University of California, Los Angeles, CA, United States
L.N. Clark
Department of Pathology and Cell Biology, College of
Physicians and Surgeons, and Taub Institute for Research
on Alzheimer’s Disease and the Aging Brain, Columbia
University, New York, NY, United States
G. Coppola
Interdepartmental Program in Bioinformatics and
Semel Institute for Neuroscience and Human
Behavior, University of California, Los Angeles,
CA, United States
M.A. Corbett
Australian Collaborative Cerebral Palsy Research
Group; Robinson Research Institute and Neurogenetics
Research Program, Adelaide Medical School,
University of Adelaide, Adelaide, South Australia,
Australia
W.T. Dauer
Department of Neurology, University of Michigan
Medical School, Ann Arbor, MI, United States
R.L. Davis
Department of Neurogenetics, Kolling Institute of
Medical Research, Royal North Shore Hospital and
University of Sydney, Sydney, NSW, Australia
A. Domingo
Institute of Neurogenetics, University of L€ubeck,
L€ubeck, Germany
T.V. Fernandez
Child Study Center, Yale School of Medicine, New
Haven, CT, United States
B.L. Fogel
Program in Neurogenetics, Departments of Neurology
and Human Genetics, David Geffen School of
Medicine, University of California, Los Angeles, CA,
United States
D.H. Geschwind
Program in Neurogenetics, Department of
Neurology, Center for Autism Research and
Treatment, Semel Institute and Department of
Human Genetics, David Geffen School of
Medicine, University of California, Los Angeles, CA,
United States
R. Ghosh
Department of Neurodegenerative Disease, UCL
Institute of Neurology, London, United Kingdom
P. Gonzalez-Alegre
Department of Neurology, University of Pennsylvania,
Philadelphia, PA, United States
D.A. Hall
Department of Neurological Sciences, Rush University,
Chicago, IL, United States
xii CONTRIBUTORS
S.J. Hayflick
Departments of Molecular and Medical Genetics,
Pediatrics and Neurology, Oregon Health and Science
University, Portland, OR, United States
P. Hogarth
Departments of Molecular and Medical Genetics and
Neurology, Oregon Health and Science University,
Portland, OR, United States
C. Klein
Institute of Neurogenetics, University of L€
ubeck,
L€ubeck, Germany
M.A. Kurian
Molecular Neurosciences, Developmental
Neurosciences Programme, Institute of Child Health,
University College London and Department of
Neurology, Great Ormond Street Hospital, London,
United Kingdom
A.R. La Spada
Department of Neurology, Duke University Medical
Center, Durham, NC, United States
C. Liang
Department of Neurogenetics, Kolling Institute of
Medical Research and Department of Neurology, Royal
North Shore Hospital, Sydney, NSW, Australia
M.T. Lorincz
Department of Neurology, University of Michigan
Health Systems, Ann Arbor, MI, United States
E.D. Louis
Taub Institute for Research on Alzheimer’s Disease and
the Aging Brain, Columbia University, New York; and
Departments of Neurology and of Chronic Disease
Epidemiology and Center for Neuroepidemiology and
Clinical Neurological Research, Yale School of
Medicine, New Haven, CT, United States
A.H. MacLennan
Australian Collaborative Cerebral Palsy Research
Group, Adelaide Medical School, and Robinson
Research Institute, University of Adelaide, Adelaide,
South Australia, Australia
M.F. Mehler
Roslyn and Leslie Goldstein Laboratory for Stem Cell
Biology and Regenerative Medicine; Institute for Brain
Disorders and Neural Regeneration; Departments of
Neurology, Neuroscience, Psychiatry and Behavioral
Sciences; Rose F. Kennedy Center for Research on
Intellectual and Developmental Disabilities; Einstein
Cancer Center; Ruth L. and David S. Gottesman Stem
Cell Institute; and Center for Epigenomics and Institute
for Aging Research, Albert Einstein College of
Medicine, Bronx, NY, United States
A. Mundwiler
Department of Neurosciences, Spectrum Health; College
of Human Medicine, Michigan State University, Grand
Rapids, MI, United States
J. Oliveira
Federal University of Pernambuco, Recife, Brazil
S.S. Pappas
Department of Neurology, University of Michigan
Medical School, Ann Arbor, MI, United States
H. Paulson
Department of Neurology, University of Michigan, Ann
Arbor, MI, United States
C. Pittenger
Child Study Center, Yale School of Medicine;
Department of Psychiatry, Yale University, New Haven,
CT, United States
F. Printzlau
Brain and Behaviour Science Unit, UCL Institute of
Child Health, London, United Kingdom
B. Quintáns
Instituto de Investigación Sanitaria (IDIS), Centro de
Investigación Biomedica en Red de Enfermedades Raras
(CIBERER), Santiago de Compostela, Spain
I.A. Qureshi
Roslyn and Leslie Goldstein Laboratory for Stem Cell
Biology and Regenerative Medicine; Institute for
Brain Disorders and Neural Regeneration;
Departments of Neurology, Neuroscience, Psychiatry
and Behavioral Sciences and Rose F. Kennedy Center for
Research on Intellectual and Developmental Disabilities,
Albert Einstein College of Medicine, Bronx, NY,
United States
G. Ramaswami
Program in Neurogenetics, Department of Neurology,
David Geffen School of Medicine, University of
California, Los Angeles, CA, United States
 CONTRIBUTORS
J.S. Roberts
Department of Health Behavior and Health Education,
University of Michigan School of Public Health; Center
for Bioethics and Social Sciences in Medicine,
University of Michigan Medical School, Ann Arbor, MI,
United States
V.G. Shakkottai
Department of Neurology, University of Michigan, Ann
Arbor, MI, United States
D. Skuse
Brain and Behaviour Science Unit, UCL Institute of
Child Health, London, United Kingdom
C.O. Smith
Department of Neurology, University of Washington,
Seattle, WA, United States
M.-J. Sobrido
Instituto de Investigación Sanitaria (IDIS), Centro de
Investigación Biomedica en Red de Enfermedades Raras
(CIBERER), Santiago de Compostela, Spain
M.W. State
Department of Psychiatry, University of California San
Francisco, San Francisco, CA, United States
C.A. Stoyas
Department of Neurology, Duke University Medical
Center, Durham, NC, United States
xiii
C.M. Sue
Department of Neurogenetics, Kolling Institute of
Medical Research and Department of Neurology, Royal
North Shore Hospital, Sydney, NSW, Australia
S.J. Tabrizi
Department of Neurodegenerative Disease, UCL
Institute of Neurology, London, United Kingdom
W.R. Uhlmann
Departments of Internal Medicine and Human Genetics;
Center for Bioethics and Social Sciences in Medicine,
University of Michigan Medical School, Ann Arbor, MI,
United States
C.L. van Eyk
Australian Collaborative Cerebral Palsy Research
Group; Robinson Research Institute and
Neurogenetics Research Program, Adelaide Medical
School, University of Adelaide, Adelaide, South
Australia, Australia
C.E. Weisheit
Department of Neurology, University of Michigan
Medical School, Ann Arbor, MI, United States
J. Wolstencroft
Brain and Behaviour Science Unit, UCL Institute of
Child Health, London, United Kingdom
This page intentionally left blank
 Contents of Part I
Foreword vii
Preface ix
Contributors xi

SECTION I Basic genetic concepts

1. Clinical approach to the patient with neurogenetic disease

T.D. Bird and C.O. Smith (Seattle, United States) 3

2. Genetic and genomic testing for neurologic disease in clinical practice

B.L. Fogel (Los Angeles, United States) 11

3. Ethical issues in neurogenetics

W.R. Uhlmann and J.S. Roberts (Ann Arbor, United States) 23

4. Evolving views of human genetic variation and its relationship to neurologic

and psychiatric disease
D.H. Geschwind (Los Angeles, United States) 37

5. Epigenetic mechanisms underlying nervous system diseases

I.A. Qureshi and M.F. Mehler (New York, United States) 43

6. Pharmacogenetics
J.R. Bishop (Minneapolis, United States) 59

7. Bioinformatics and genomic databases

J. Chen and G. Coppola (Los Angeles, United States) 75

8. Towards precision medicine

T. Bardakjian and P. Gonzalez-Alegre (Philadelphia, United States) 93

SECTION II Recurring biological themes in neurogenetics

9. Repeat expansion diseases

H. Paulson (Ann Arbor, United States) 105

10. Mitochondrial diseases

R.L. Davis, C. Liang, and C.M. Sue (Sydney, Australia) 125

11. The CAG–polyglutamine repeat diseases: a clinical, molecular, genetic,

and pathophysiologic nosology
C.A. Stoyas and A.R. La Spada (Durham, United States) 143

SECTION III Movement disorders

12. Autosomal-dominant cerebellar ataxias

A. Mundwiler and V.G. Shakkottai (Grand Rapids and Ann Arbor, United States) 173
xvi CONTENTS OF PART I
13. Autosomal-recessive cerebellar ataxias
B.L. Fogel (Los Angeles, United States) 187

14. Genetics of Parkinson disease

A. Domingo and C. Klein (L€
ubeck, Germany) 211

15. Essential tremor

L.N. Clark and E.D. Louis (New York and New Haven, United States) 229

16. Inherited dystonias: clinical features and molecular pathways

C.E. Weisheit, S.S. Pappas, and W.T. Dauer (Ann Arbor, United States) 241

17. Huntington disease

R. Ghosh and S.J. Tabrizi (London, United Kingdom) 255

18. Wilson disease and related copper disorders

M.T. Lorincz (Ann Arbor, United States) 279

19. Neurodegeneration with brain iron accumulation

S.J. Hayflick, M.A. Kurian, and P. Hogarth (Portland, United States and London, United Kingdom) 293

20. Primary familial brain calcifications

B. Quintáns, J. Oliveira, and M.-J. Sobrido (Santiago de Compostela, Spain and Recife, Brazil) 307

SECTION IV Neurodevelopmental disorders

21. Genetics of autism spectrum disorder

G. Ramaswami and D.H. Geschwind (Los Angeles, United States) 321

22. The emerging genetic landscape of cerebral palsy

C.L. van Eyk, M.A. Corbett, and A.H. MacLennan (Adelaide, Australia) 331

23. Tourette disorder and other tic disorders

T.V. Fernandez, M.W. State, and C. Pittenger (New Haven and San Francisco, United States) 343

24. Sex chromosome aneuploidies

D. Skuse, F. Printzlau, and J. Wolstencroft (London, United Kingdom) 355

25. Fragile X syndrome and fragile X-associated tremor ataxia syndrome

D.A. Hall and E. Berry-Kravis (Chicago, United States) 377

Index I-1
 Contents of Part II
Foreword vii
Preface ix
Contributors xi

SECTION V Dementias

26. The genetic landscape of Alzheimer disease

S. Carmona, J. Hardy, and R. Guerreiro (London, United Kingdom and Aveiro, Portugal) 395

27. Frontotemporal dementia

J. Deleon and B.L. Miller (San Francisco, United States) 409

28. The genetics of dementia with Lewy bodies

M.I. Tolea and J.E. Galvin (Boca Raton, United States) 431

29. Prion disease

L.T. Takada, M.-O. Kim, S. Metcalf, I. Illán Gala, and M.D. Geschwind
(São Paulo, Brazil, San Francisco, United States and Barcelona, Spain) 441

SECTION VI Paroxysmal disorders

30. Genetics of epilepsy

D. Nolan and J. Fink (Ann Arbor, United States) 467

31. Genetics of migraine

V. Anttila, M. Wessman, M. Kallela, and A. Palotie
(Boston and Cambridge, United States and Helsinki, Finland) 493

32. Periodic paralysis

D. Fialho, R.C. Griggs, and E. Matthews (London, United Kingdom and Rochester, United States) 505

33. Episodic ataxias

J.C. Jen and J. Wan (Los Angeles, United States) 521

34. Disorders of sleep and circadian rhythms

S.Y.C. Chong, L. Xin, L.J. Ptáček, and Y.-H. Fu (San Francisco, United States) 531

SECTION VII Neuromuscular disorders

35. Facioscapulohumeral muscular dystrophy

R. Tawil (Rochester, United States) 541

36. The genetics of congenital myopathies

H.D. Gonorazky, C.G. B€onnemann, and J.J. Dowling (Toronto, Canada and Bethesda, United States) 549
xviii CONTENTS OF PART II
37. Genetic basis and phenotypic features of congenital myasthenic syndromes
A.G. Engel (Rochester, United States) 565

38. Spinal muscular atrophy

E.S. Arnold and K.H. Fischbeck (Bethesda, United States) 591

39. Emerging understanding of the genotype–phenotype relationship in amyotrophic lateral sclerosis

S.A. Goutman, K.S. Chen, X. Paez-Colasante, and E.L. Feldman (Ann Arbor, United States) 603

40. Spinal and bulbar muscular atrophy

A.P. Lieberman (Ann Arbor, United States) 625

41. Hereditary spastic paraplegia

C. Blackstone (Bethesda, United States) 633

42. Neuropathy
C. Pisciotta and M.E. Shy (Iowa City, United States) 653

SECTION VIII Diseases of white matter and demyelination

43. The spectrum of adult-onset heritable white-matter disorders

G. Helman, S. Venkateswaran, and A. Vanderver (Brisbane, Australia, Ottawa, Canada,
and Philadelphia and Washington, United States) 669

44. Alexander disease

A. Messing (Madison, United States) 693

45. Neurogenetics of Pelizaeus–Merzbacher disease

M.J. Osório and S.A. Goldman (Rochester, United States and Copenhagen, Denmark) 701

46. Multiple sclerosis

C. Cotsapas, M. Mitrovic, and D. Hafler (New Haven, United States) 723

SECTION IX Cerebrovascular diseases

47. CADASIL
M.M. Wang (Ann Arbor, United States) 733

SECTION X Major adult psychiatric disorders

48. Neuroepigenetics and addiction

D.M. Walker and E.J. Nestler (New York, United States) 747

49. Genetic susceptibility in obsessive-compulsive disorder

T.V. Fernandez, J.F. Leckman, and C. Pittenger (New Haven, United States) 767

SECTION XI Cancer and phakomatoses

50. Brain cancer genomics and epigenomics

T.C. Archer, S. Sengupta, and S.L. Pomeroy (Boston, Cambridge and Atlanta, United States) 785

51. Neurofibromatosis type 1

P.J. Cimino and D.H. Gutmann (Seattle and St. Louis, United States) 799
 CONTENTS OF PART II xix
52. Tuberous sclerosis complex
D.M. Hasbani and P.B. Crino (Philadelphia and Baltimore, United States) 813

53. Von Hippel–Lindau disease and Sturge–Weber syndrome

S. Perlman (Los Angeles, United States) 823

Index I-1
This page intentionally left blank
 Section I

Basic genetic concepts

This page intentionally left blank
Handbook of Clinical Neurology, Vol. 147 (3rd series)
Neurogenetics, Part I
D.H. Geschwind, H.L. Paulson, and C. Klein, Editors
https://doi.org/10.1016/B978-0-444-63233-3.00001-4
Copyright © 2018 Elsevier B.V. All rights reserved

Chapter 1

Clinical approach to the patient with neurogenetic disease

THOMAS D. BIRD1,2* AND CORRIE O. SMITH1
1
Department of Neurology, University of Washington, Seattle, WA, United States
2
Geriatric Research Center, VA Medical Center, Seattle, WA, United States

Abstract
Neurogenetic diseases are surprisingly common. This chapter reviews a systematic approach to the eval-
uation of a patient thought to have such a disease. The emphasis is on first recognizing potential clues to the
diagnosis contained in the family history and presentation of symptoms. Ataxia, neuropathy, muscle weak-
ness, dementia, epilepsy, and cognitive delay are all “reservoirs” of neurogenetic disease. A high index of
suspicion for genetic causes and a thoughtful evaluation of simplex (sporadic) cases is often necessary.
Then the physician can proceed to the differential diagnosis, genetic testing, and genetic counseling.
A team approach including a genetic counselor is usually the best strategy.

The clinical practice of neurogenetics is complex, chal-
lenging, and rewarding, and becoming increasingly rel-
evant with advances in genetic testing and diagnosis.
This chapter will focus on eight aspects of clinical neu-
rogenetics: (1) factors suggesting the presence of a
genetic disease; (2) nonspecific diagnoses that may be
masking neurogenetic diseases; (3) the importance of
family history; (4) the assessment of sporadic cases;
(5) genetic counseling; (6) genetic testing; (7) available
information resources; and (8) integration of the clinical
neurogenetic strategy. (A discussion of this approach has
appeared previously, in Bird, 2002.)
FACTORS SUGGESTING A
NEUROGENETIC DISORDER
Table 1.1 highlights clues indicating an increased prob-
ability that a patient may have a neurogenetic disorder.
Not surprisingly, first and foremost is the presence of a
positive family history. By nature, genetic diseases are
usually inherited. Thus it is typical to observe other
affected family members. This is true of all patterns of
inheritance, including autosomal-dominant, autosomal-
recessive, X-linked, and mitochondrial. Therefore, a pos-
itive family history of a similarly affected individual is a
compelling sign of a genetic disorder. However, there are
two major exceptions to finding a positive family history.
The first is that isolated or sporadic cases without a pos-
itive family history can still be genetic. The various
explanations for sporadic cases of genetic disease are
explained later in this chapter. The second exception is
that familial disorders are not necessarily genetic. For
example, family members sharing the same environment
may be affected with the same nongenetic acquired dis-
ease (such as neuropathy or ataxia), because of common
exposure to infectious or toxic agents. Another example
is the presence of older family members affected with a
prevalent age-related condition such as Alzheimer dis-
ease or cataracts. It is important to remember that,
although a positive family history is a strong sign of a
genetic disease, familial disorders are not always genetic
and genetic disorders are not always familial.
Probably the next most important clue suggesting a
genetic disorder is a constellation of signs and symptoms
suggesting a known genetic syndrome. This is common
sense, but often requires a detailed knowledge of, and
memory for, syndromic identification. For example,
atypical facial “acne” and a seizure disorder suggest
tuberous sclerosis, progressive ataxia with loss of
reflexes suggests Friedreich ataxia, white-matter disease

*Correspondence to: Thomas D. Bird, MD, Puget Sound Health Care System, S-182-GRECC, 1660 South Columbian Way, Seattle
WA 98108, United States. Tel: +1-206-764-2308, Fax: +1-206-764-2569, E-mail: tomnroz@u.washington.edu
4 T.D. BIRD AND C.O. SMITH
Table 1.1
Clues to the presence of a neurogenetic disease
● Positive family history
● Similarity to a known genetic syndrome
● Chronic, progressive clinical course
● Consanguinity
● Increased frequency in a specific ethnic group
Table 1.2
Diagnostic reservoirs of neurogenetic diseases
● Cerebral palsy
●
Mental retardation
● Epilepsy
● Movement disorders
● Ataxias
● Dementias
● Atypical multiple sclerosis
● Peripheral neuropathy
with hyperactive tendon reflexes in a male suggest adre-
noleukodystrophy or Pelizaeus–Merzbacher disease, and
muscle weakness associated with muscle cramps and cat-
aracts suggests myotonic dystrophy.
Other factors suggesting a genetic disease are less
clear but often helpful. For example, most genetic dis-
eases have a slow, subtle onset and prolonged,
chronic course. Many have onset in childhood, although
it is not uncommon to have a later onset, especially
with autosomal-dominant conditions. Consanguinity (mat-
ings between blood relatives) is a clue to autosomal-
recessive disorders. Also, certain diseases are more
common in specific ethnic groups. Examples would be
Tay–Sachs disease in Eastern European (Ashkenazi)
Jews, Unverricht–Lundborg myoclonic epilepsy in Finns,
dentatorubral-pallidoluysian atrophy in Japanese, spino-
cerebellar ataxia type 3 in Portuguese, and cerebral
cavernous malformations or spinocerebellar ataxia type
10 in Mexicans.
NONSPECIFIC CATEGORIES MASKING
NEUROGENETIC DISEASES
Certain nonspecific diagnostic categories often harbor
patients with neurogenetic diseases and can be viewed
as “reservoirs” where neurogenetic patients may be
“hiding.” Several of these categories are listed in
Table 1.2. These categories are quite general and such
diagnoses may indicate a lack of thorough diagnostic
evaluation when applied to individual patients. This is
particularly true of cerebral palsy, epilepsy, intellectual
disability, and multiple sclerosis (MS). Certainly, any
patient with one of these diagnoses and with a positive
family history of a similarly affected individual should
initiate a further search for a more specific genetic cause.
We have seen patients with a diagnosis of cerebral palsy
actually discovered to have familial spastic paraplegia,
ataxia telangiectasia, or Pelizaeus–Merzbacher disease.
Patients with nonspecific dementia have been found to
have genetic forms of Alzheimer disease, Creutzfeldt–
Jacob disease, and frontotemporal dementia. Patients
with a diagnosis of MS have been rediagnosed with cere-
bral autosomal-dominant arteriopathy with subcortical
infarcts and leukoencephalopathy (CADASIL) and a
variety of genetic leukodystrophies. Persons with move-
ment disorders of uncertain cause have been found to
have Huntington disease, hereditary ataxias, and genetic
forms of dystonia. More detailed evaluation of
patients with unexplained epilepsy has uncovered cases
of myoclonic epilepsy with ragged red fibers and
autosomal-recessive myoclonic epilepsy. Many patients
with Charcot–Marie–Tooth (CMT) disease have a diag-
nosis of peripheral neuropathy without recognition of its
genetic nature.
IMPORTANCE OF FAMILY HISTORY
Because a positive family history is such an important
element in the diagnosis of neurogenetic disorders it is
critical to pay careful attention to the family story and
to record it appropriately for future reference (Bennett,
2009). The clinician should always inquire about the
health of siblings, parents, and children. If clues begin
to accumulate that a genetic disease may be present, then
one inquires about more distant relatives such as grand-
parents, aunts, uncles, and cousins. Not only is it impor-
tant to inquire about numerous family members, but the
types of questions need to be carefully tailored to the
differential diagnosis. For example, if considering myo-
tonic muscular dystrophy, you would ask about other
family members with muscle weakness, cardiac arrhyth-
mias, baldness, diabetes, developmental delay, or cata-
ract. If considering CMT neuropathy the questions
would include difficulty walking, high arched feet,
braces, or foot surgery. Concern about the diagnosis of
neurofibromatosis type 1 would initiate questions about
skin spots and skin lumps and the possibility of tuberous
sclerosis would trigger questions about intellectual dis-
ability, seizures, skin lesions, and kidney disease.
A broad knowledge of the various possible syndromes
is critical because nonobvious questions may become
important: for example, the association of berry aneu-
rysm with autosomal-dominant polycystic kidney dis-
ease, diabetes and gallbladder disease with myotonic
dystrophy, schizophrenia with Huntington disease,
and frontotemporal dementia and amyotrophic lateral
sclerosis in families with repeat expansions in the
C9ORF72 gene.
Another random document with
no related content on Scribd:
 TRANSCRIBER’S NOTES:
Obvious typographical errors have been corrected.
Inconsistencies in hyphenation have been
standardized.
Archaic or variant spelling has been retained.
*** END OF THE PROJECT GUTENBERG EBOOK THE HISTORY
OF COMPANY B, 311TH INFANTRY IN THE WORLD WAR ***

Updated editions will replace the previous one—the old editions

will be renamed.

Creating the works from print editions not protected by U.S.

copyright law means that no one owns a United States copyright
in these works, so the Foundation (and you!) can copy and
distribute it in the United States without permission and without
paying copyright royalties. Special rules, set forth in the General
Terms of Use part of this license, apply to copying and
distributing Project Gutenberg™ electronic works to protect the
PROJECT GUTENBERG™ concept and trademark. Project
Gutenberg is a registered trademark, and may not be used if
you charge for an eBook, except by following the terms of the
trademark license, including paying royalties for use of the
Project Gutenberg trademark. If you do not charge anything for
copies of this eBook, complying with the trademark license is
very easy. You may use this eBook for nearly any purpose such
as creation of derivative works, reports, performances and
research. Project Gutenberg eBooks may be modified and
printed and given away—you may do practically ANYTHING in
the United States with eBooks not protected by U.S. copyright
law. Redistribution is subject to the trademark license, especially
commercial redistribution.

START: FULL LICENSE

THE FULL PROJECT GUTENBERG LICENSE
 PLEASE READ THIS BEFORE YOU DISTRIBUTE OR USE THIS WORK

To protect the Project Gutenberg™ mission of promoting the

free distribution of electronic works, by using or distributing this
work (or any other work associated in any way with the phrase
“Project Gutenberg”), you agree to comply with all the terms of
the Full Project Gutenberg™ License available with this file or
online at www.gutenberg.org/license.

Section 1. General Terms of Use and

Redistributing Project Gutenberg™
electronic works
1.A. By reading or using any part of this Project Gutenberg™
electronic work, you indicate that you have read, understand,
agree to and accept all the terms of this license and intellectual
property (trademark/copyright) agreement. If you do not agree to
abide by all the terms of this agreement, you must cease using
and return or destroy all copies of Project Gutenberg™
electronic works in your possession. If you paid a fee for
obtaining a copy of or access to a Project Gutenberg™
electronic work and you do not agree to be bound by the terms
of this agreement, you may obtain a refund from the person or
entity to whom you paid the fee as set forth in paragraph 1.E.8.

1.B. “Project Gutenberg” is a registered trademark. It may only

be used on or associated in any way with an electronic work by
people who agree to be bound by the terms of this agreement.
There are a few things that you can do with most Project
Gutenberg™ electronic works even without complying with the
full terms of this agreement. See paragraph 1.C below. There
are a lot of things you can do with Project Gutenberg™
electronic works if you follow the terms of this agreement and
help preserve free future access to Project Gutenberg™
electronic works. See paragraph 1.E below.
1.C. The Project Gutenberg Literary Archive Foundation (“the
Foundation” or PGLAF), owns a compilation copyright in the
collection of Project Gutenberg™ electronic works. Nearly all the
individual works in the collection are in the public domain in the
United States. If an individual work is unprotected by copyright
law in the United States and you are located in the United
States, we do not claim a right to prevent you from copying,
distributing, performing, displaying or creating derivative works
based on the work as long as all references to Project
Gutenberg are removed. Of course, we hope that you will
support the Project Gutenberg™ mission of promoting free
access to electronic works by freely sharing Project
Gutenberg™ works in compliance with the terms of this
agreement for keeping the Project Gutenberg™ name
associated with the work. You can easily comply with the terms
of this agreement by keeping this work in the same format with
its attached full Project Gutenberg™ License when you share it
without charge with others.

1.D. The copyright laws of the place where you are located also
govern what you can do with this work. Copyright laws in most
countries are in a constant state of change. If you are outside
the United States, check the laws of your country in addition to
the terms of this agreement before downloading, copying,
displaying, performing, distributing or creating derivative works
based on this work or any other Project Gutenberg™ work. The
Foundation makes no representations concerning the copyright
status of any work in any country other than the United States.

1.E. Unless you have removed all references to Project

Gutenberg:

1.E.1. The following sentence, with active links to, or other

immediate access to, the full Project Gutenberg™ License must
appear prominently whenever any copy of a Project
Gutenberg™ work (any work on which the phrase “Project
Gutenberg” appears, or with which the phrase “Project
Gutenberg” is associated) is accessed, displayed, performed,
viewed, copied or distributed:

This eBook is for the use of anyone anywhere in the United

States and most other parts of the world at no cost and with
almost no restrictions whatsoever. You may copy it, give it
away or re-use it under the terms of the Project Gutenberg
License included with this eBook or online at
www.gutenberg.org. If you are not located in the United
States, you will have to check the laws of the country where
you are located before using this eBook.

1.E.2. If an individual Project Gutenberg™ electronic work is

derived from texts not protected by U.S. copyright law (does not
contain a notice indicating that it is posted with permission of the
copyright holder), the work can be copied and distributed to
anyone in the United States without paying any fees or charges.
If you are redistributing or providing access to a work with the
phrase “Project Gutenberg” associated with or appearing on the
work, you must comply either with the requirements of
paragraphs 1.E.1 through 1.E.7 or obtain permission for the use
of the work and the Project Gutenberg™ trademark as set forth
in paragraphs 1.E.8 or 1.E.9.

1.E.3. If an individual Project Gutenberg™ electronic work is

posted with the permission of the copyright holder, your use and
distribution must comply with both paragraphs 1.E.1 through
1.E.7 and any additional terms imposed by the copyright holder.
Additional terms will be linked to the Project Gutenberg™
License for all works posted with the permission of the copyright
holder found at the beginning of this work.

1.E.4. Do not unlink or detach or remove the full Project

Gutenberg™ License terms from this work, or any files
containing a part of this work or any other work associated with
Project Gutenberg™.
 1.E.5. Do not copy, display, perform, distribute or redistribute
this electronic work, or any part of this electronic work, without
prominently displaying the sentence set forth in paragraph 1.E.1
with active links or immediate access to the full terms of the
Project Gutenberg™ License.

1.E.6. You may convert to and distribute this work in any binary,
compressed, marked up, nonproprietary or proprietary form,
including any word processing or hypertext form. However, if
you provide access to or distribute copies of a Project
Gutenberg™ work in a format other than “Plain Vanilla ASCII” or
other format used in the official version posted on the official
Project Gutenberg™ website (www.gutenberg.org), you must, at
no additional cost, fee or expense to the user, provide a copy, a
means of exporting a copy, or a means of obtaining a copy upon
request, of the work in its original “Plain Vanilla ASCII” or other
form. Any alternate format must include the full Project
Gutenberg™ License as specified in paragraph 1.E.1.

1.E.7. Do not charge a fee for access to, viewing, displaying,

performing, copying or distributing any Project Gutenberg™
works unless you comply with paragraph 1.E.8 or 1.E.9.

1.E.8. You may charge a reasonable fee for copies of or

providing access to or distributing Project Gutenberg™
electronic works provided that:

• You pay a royalty fee of 20% of the gross profits you derive from
the use of Project Gutenberg™ works calculated using the
method you already use to calculate your applicable taxes. The
fee is owed to the owner of the Project Gutenberg™ trademark,
but he has agreed to donate royalties under this paragraph to
the Project Gutenberg Literary Archive Foundation. Royalty
payments must be paid within 60 days following each date on
which you prepare (or are legally required to prepare) your
periodic tax returns. Royalty payments should be clearly marked
as such and sent to the Project Gutenberg Literary Archive
Foundation at the address specified in Section 4, “Information
 about donations to the Project Gutenberg Literary Archive
Foundation.”

• You provide a full refund of any money paid by a user who

notifies you in writing (or by e-mail) within 30 days of receipt that
s/he does not agree to the terms of the full Project Gutenberg™
License. You must require such a user to return or destroy all
copies of the works possessed in a physical medium and
discontinue all use of and all access to other copies of Project
Gutenberg™ works.

• You provide, in accordance with paragraph 1.F.3, a full refund of

any money paid for a work or a replacement copy, if a defect in
the electronic work is discovered and reported to you within 90
days of receipt of the work.

• You comply with all other terms of this agreement for free
distribution of Project Gutenberg™ works.

1.E.9. If you wish to charge a fee or distribute a Project

Gutenberg™ electronic work or group of works on different
terms than are set forth in this agreement, you must obtain
permission in writing from the Project Gutenberg Literary
Archive Foundation, the manager of the Project Gutenberg™
trademark. Contact the Foundation as set forth in Section 3
below.

1.F.

1.F.1. Project Gutenberg volunteers and employees expend

considerable effort to identify, do copyright research on,
transcribe and proofread works not protected by U.S. copyright
law in creating the Project Gutenberg™ collection. Despite
these efforts, Project Gutenberg™ electronic works, and the
medium on which they may be stored, may contain “Defects,”
such as, but not limited to, incomplete, inaccurate or corrupt
data, transcription errors, a copyright or other intellectual
property infringement, a defective or damaged disk or other
medium, a computer virus, or computer codes that damage or
cannot be read by your equipment.

1.F.2. LIMITED WARRANTY, DISCLAIMER OF DAMAGES -

Except for the “Right of Replacement or Refund” described in
paragraph 1.F.3, the Project Gutenberg Literary Archive
Foundation, the owner of the Project Gutenberg™ trademark,
and any other party distributing a Project Gutenberg™ electronic
work under this agreement, disclaim all liability to you for
damages, costs and expenses, including legal fees. YOU
AGREE THAT YOU HAVE NO REMEDIES FOR NEGLIGENCE,
STRICT LIABILITY, BREACH OF WARRANTY OR BREACH
OF CONTRACT EXCEPT THOSE PROVIDED IN PARAGRAPH
1.F.3. YOU AGREE THAT THE FOUNDATION, THE
TRADEMARK OWNER, AND ANY DISTRIBUTOR UNDER
THIS AGREEMENT WILL NOT BE LIABLE TO YOU FOR
ACTUAL, DIRECT, INDIRECT, CONSEQUENTIAL, PUNITIVE
OR INCIDENTAL DAMAGES EVEN IF YOU GIVE NOTICE OF
THE POSSIBILITY OF SUCH DAMAGE.

1.F.3. LIMITED RIGHT OF REPLACEMENT OR REFUND - If

you discover a defect in this electronic work within 90 days of
receiving it, you can receive a refund of the money (if any) you
paid for it by sending a written explanation to the person you
received the work from. If you received the work on a physical
medium, you must return the medium with your written
explanation. The person or entity that provided you with the
defective work may elect to provide a replacement copy in lieu
of a refund. If you received the work electronically, the person or
entity providing it to you may choose to give you a second
opportunity to receive the work electronically in lieu of a refund.
If the second copy is also defective, you may demand a refund
in writing without further opportunities to fix the problem.

1.F.4. Except for the limited right of replacement or refund set

forth in paragraph 1.F.3, this work is provided to you ‘AS-IS’,
WITH NO OTHER WARRANTIES OF ANY KIND, EXPRESS
OR IMPLIED, INCLUDING BUT NOT LIMITED TO
WARRANTIES OF MERCHANTABILITY OR FITNESS FOR
ANY PURPOSE.

1.F.5. Some states do not allow disclaimers of certain implied

warranties or the exclusion or limitation of certain types of
damages. If any disclaimer or limitation set forth in this
agreement violates the law of the state applicable to this
agreement, the agreement shall be interpreted to make the
maximum disclaimer or limitation permitted by the applicable
state law. The invalidity or unenforceability of any provision of
this agreement shall not void the remaining provisions.

1.F.6. INDEMNITY - You agree to indemnify and hold the

Foundation, the trademark owner, any agent or employee of the
Foundation, anyone providing copies of Project Gutenberg™
electronic works in accordance with this agreement, and any
volunteers associated with the production, promotion and
distribution of Project Gutenberg™ electronic works, harmless
from all liability, costs and expenses, including legal fees, that
arise directly or indirectly from any of the following which you do
or cause to occur: (a) distribution of this or any Project
Gutenberg™ work, (b) alteration, modification, or additions or
deletions to any Project Gutenberg™ work, and (c) any Defect
you cause.

Section 2. Information about the Mission of

Project Gutenberg™
Project Gutenberg™ is synonymous with the free distribution of
electronic works in formats readable by the widest variety of
computers including obsolete, old, middle-aged and new
computers. It exists because of the efforts of hundreds of
volunteers and donations from people in all walks of life.

Volunteers and financial support to provide volunteers with the

assistance they need are critical to reaching Project
Gutenberg™’s goals and ensuring that the Project Gutenberg™
collection will remain freely available for generations to come. In
2001, the Project Gutenberg Literary Archive Foundation was
created to provide a secure and permanent future for Project
Gutenberg™ and future generations. To learn more about the
Project Gutenberg Literary Archive Foundation and how your
efforts and donations can help, see Sections 3 and 4 and the
Foundation information page at www.gutenberg.org.

Section 3. Information about the Project

Gutenberg Literary Archive Foundation
The Project Gutenberg Literary Archive Foundation is a non-
profit 501(c)(3) educational corporation organized under the
laws of the state of Mississippi and granted tax exempt status by
the Internal Revenue Service. The Foundation’s EIN or federal
tax identification number is 64-6221541. Contributions to the
Project Gutenberg Literary Archive Foundation are tax
deductible to the full extent permitted by U.S. federal laws and
your state’s laws.

The Foundation’s business office is located at 809 North 1500

West, Salt Lake City, UT 84116, (801) 596-1887. Email contact
links and up to date contact information can be found at the
Foundation’s website and official page at
www.gutenberg.org/contact

Section 4. Information about Donations to

the Project Gutenberg Literary Archive
Foundation
Project Gutenberg™ depends upon and cannot survive without
widespread public support and donations to carry out its mission
of increasing the number of public domain and licensed works
that can be freely distributed in machine-readable form
accessible by the widest array of equipment including outdated
equipment. Many small donations ($1 to $5,000) are particularly
important to maintaining tax exempt status with the IRS.

The Foundation is committed to complying with the laws

regulating charities and charitable donations in all 50 states of
the United States. Compliance requirements are not uniform
and it takes a considerable effort, much paperwork and many
fees to meet and keep up with these requirements. We do not
solicit donations in locations where we have not received written
confirmation of compliance. To SEND DONATIONS or
determine the status of compliance for any particular state visit
www.gutenberg.org/donate.

While we cannot and do not solicit contributions from states

where we have not met the solicitation requirements, we know
of no prohibition against accepting unsolicited donations from
donors in such states who approach us with offers to donate.

International donations are gratefully accepted, but we cannot

make any statements concerning tax treatment of donations
received from outside the United States. U.S. laws alone swamp
our small staff.

Please check the Project Gutenberg web pages for current

donation methods and addresses. Donations are accepted in a
number of other ways including checks, online payments and
credit card donations. To donate, please visit:
www.gutenberg.org/donate.

Section 5. General Information About Project

Gutenberg™ electronic works
Professor Michael S. Hart was the originator of the Project
Gutenberg™ concept of a library of electronic works that could
be freely shared with anyone. For forty years, he produced and
distributed Project Gutenberg™ eBooks with only a loose
network of volunteer support.

Project Gutenberg™ eBooks are often created from several

printed editions, all of which are confirmed as not protected by
copyright in the U.S. unless a copyright notice is included. Thus,
we do not necessarily keep eBooks in compliance with any
particular paper edition.

Most people start at our website which has the main PG search
facility: www.gutenberg.org.

This website includes information about Project Gutenberg™,

including how to make donations to the Project Gutenberg
Literary Archive Foundation, how to help produce our new
eBooks, and how to subscribe to our email newsletter to hear
about new eBooks.