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ROSENBERG’S MOLECULAR AND GENETIC BASIS OF
NEUROLOGICAL AND PSYCHIATRIC DISEASE
ROSENBERG’S
MOLECULAR AND
GENETIC BASIS OF
NEUROLOGICAL AND
PSYCHIATRIC DISEASE
VOLUME 1
SIXTH EDITION
Edited by
ROGER N. ROSENBERG
The University of Texas Southwestern Medical Center, UT Southwestern University Hospitals and Clinics,
Parkland Memorial Hospital, Dallas, TX, United States
JUAN M. PASCUAL
The University of Texas Southwestern Medical Center, UT Southwestern University Hospitals and Clinics,
Parkland Memorial Hospital, Children’s Medical Center, Dallas, TX, United States
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Dedication
We dedicate this text to our colleagues, who, by perseverance and dedication, have provided essential new scientific knowl-
edge about the molecular and genetic basis of neurologic and psychiatric disorders, and, in so doing, have conceptualized
important insights into disease causation and therapies for the future.
Roger N. Rosenberg and Juan M. Pascual
I wish to dedicate this work to my parents, Cora and Sol Rosenberg, and to my wife, Adrienne. They have been an inspira-
tion to me and have provided me with their care and love to maintain my focus and resilience throughout my life and career,
for which I will forever be grateful.
Roger N. Rosenberg
Juan M. Pascual dedicates this work to his mother, Guadalupe Fernández Ariza, a distinguished scholar, from whom he con-
tinues to learn everything worth knowing:
If you follow my advice, first of all I shall show you many works of men of old, tell you their wondrous deeds and words, and
make you conversant with almost all knowledge, and I shall ornament your soul, which concerns you most, with many noble adorn-
ments —temperance, justice, piety, kindliness, reasonableness, understanding, steadfastness, love of all that is beautiful, ardour towards
all that is sublime; for these are the truly flawless jewels of the soul. Nothing that came to pass of old will escape you, and nothing that
must now come to pass; nay, you will even foresee the future with me. In a word, I shall speedily teach you everything that there is,
whether it pertains to the gods or to man. . . They say that some men become immortal. I shall bring this to pass with you; for though
you yourself depart from life, you will never cease associating with men of education and conversing with men of eminence.
Lucian. The Dream or Lucian’s Career. Translated by A. M. Harmon. Loeb Classical Library 130. Cambridge, MA: Harvard University
Press, 1921.
Contents
List of contributors xvii 3. Epigenomics of neurological disorders

Foreword xxi OLGA KHORKOVA, JANE HSIAO AND CLAES WAHLESTEDT
Prologue xxiii
Introduction 41
Introduction xxv Types and mechanisms of epigenetic modifications 41
Epigenetic targets in neurological disorders 43
Conclusions 52
I References 53
General concepts and tools
1. Mendelian, non-Mendelian, multigenic 4. Genotype phenotype considerations in

inheritance, and epigenetics neurogenetic disease
TAMAR HAREL AND JAMES R. LUPSKI BRENT L. FOGEL
Introduction 3 Introduction 59
Mendelian traits 3 Genotype and phenotype: definition and clinical usage 60
Repeat expansion disorders 7 Penetrance 63
Non-Mendelian inheritance 8 Expressivity 64
Chromosomal and genomic disorders 10 Clinical heterogeneity 64
Multigenic inheritance 16 Complex disease and polygenic risk 65
Complex traits 17 Genotype phenotype considerations for the neurogenetic
Epigenetics 19 evaluation 66
The human genome: next-generation sequencing 21 Conclusion 66
Conclusion 21 Funding 67
References 22 Conflict of interest 67
References 67
2. Precision medicine in neurology

C. THOMAS CASKEY, JENNIFER E. POSEY, YING-CHEN CLAIRE HOU
AND HUNG-CHUN YU
5. Immunogenetics of neurological disease
Introduction 27 PHILIP L. DE JAGER
Technologies contributing to precision medicine 27
Metabolomics 29 Introduction 71
Imaging 30 Lessons from immunogenetics 71
Wearable devices 30 Immune cell states 74
Early precision medicine advancements 31 Major histocompatibility complex 75
Initiation of precision medicine programs in the United States 32 Neurodegeneration and the immune system 76
Precision medicine results at individualized level (N-of-1) 32 Neurologic adverse events from immunotherapy: role of
Pharmacogenetics 34 immunogenetics 78
Incorporation of precision diagnostics with targeted therapy 36 Immunosenescence 78
Summary 37 Immunogenetics and the future of neurologic disease 79
References 37 References 79
vii
viii CONTENTS
6. Pharmacogenomic approaches to the treatment Part I: Development of adeno-associated virus as a central

of sporadic Alzheimer’s disease nervous system gene transfer vector 129
Part II: Preclinical advancements in central nervous system
JUDES POIRIER, NATHALIE NILSSON, MARINA TEDESCHI DAUAR,
JUSTIN MIRON AND CYNTHIA PICARD disorders using adeno-associated virus gene therapy 132
Part III: Clinical translation, milestones, and challenges 136
Genetic risk factors and sporadic Alzheimer’s disease 81 Conclusion 139
Genetic risk factors, cholinergic dysfunction and Alzheimer’s Acknowledgment 139
disease 82 References 139
Apolipoprotein E type 4 and cholinomimetic drugs in
Alzheimer’s disease 82
Experimental drugs and their relationship to the
apolipoprotein E type 4 allele 86 11. Genomics of human neurological disorders
Acetylcholinesterase and butyrylcholinesterase genetic ROBERT L. NUSSBAUM
variants in dementia 88
Pharmacogenomics of adverse side effects 90 Genome annotation 145
Acknowledgments 91 Applying human genomics to understanding disorders of the
References 91 nervous system 151
References 155
7. Application of mouse genetics to human disease:

generation and analysis of mouse models
TERESA M. GUNN AND BRENDA CANINE
12. CRISPR Cas immune systems and genome
engineering
Creating mouse models 96 SANNE E. KLOMPE AND SAMUEL H. STERNBERG
Phenotypic analysis of mouse models 103
Summary 106 General mechanism of CRISPR Cas immunity 158
References 106 CRISPR Cas diversity and classification 159
Mechanisms of RNA-guided nucleic acid targeting 160
Expanding the CRISPR Cas toolbox 164
8. DNA sequencing and other methods of exonic Applications of CRISPR Cas to neurological disease 169
and genomic analyses Concluding thoughts 169
JUN MITSUI, HIROYUKI ISHIURA AND SHOJI TSUJI Disclosure 170
References 170
DNA sequencing technologies 109
Application of next-generation sequencing to elucidating
Mendelian-trait diseases 113
Application of next-generation sequencing to clinical 13. Direct induction of neural cells from somatic
sequencing 115 cells
Other methods of exonic and genomic analysis 115 WADO AKAMATSU AND HIDEYUKI OKANO
New technologies for haplotyping 118
References 118 Introduction 179
Direct induction of neural stem cells from somatic cells 180
Differentiation properties of induced neural stem cells 180
9. Association, cause, and causal association, Comparison of direct induction into neural stem cells 180
revised: reasoning and methods Direct induction of neurons from somatic cells 181
WALTER A. KUKULL Direct induction in regenerative medicine 183
References 183
Learning from infectious disease 121
Causal “guidelines” and observational versus experimental
designs 122
The progression of complexity into public health 126 14. Neuroimaging in dementias
References 127 PRASHANTHI VEMURI, CLIFFORD R. JACK JR. AND
MELISSA E. MURRAY
10. Adeno-associated virus-mediated gene Neuroimaging technologies 187

therapy in central nervous system genetic disorders Alzheimer’s disease 189
WIDLER CASY, QINGLAN LING, FRANCES C. SHAFFO, SARAH E. SINNETT Dementia with Lewy bodies 192
AND STEVEN J. GRAY Frontotemporal dementia 193
Imaging cerebrovascular disease 195
Introduction 129 References 195
CONTENTS ix
15. Cognitive enhancers, intellectual disability, and Neuronal heterotopia 262
personal identity: emerging ethical issues References 264
FABRICE JOTTERAND, JENNIFER MCCURDY AND BERNICE ELGER
Introduction 199 19. Global developmental delay and intellectual

Neuroethics in context 200 disability
Therapy enhancement: a false dichotomy 200 MYRIAM SROUR, AFNAN ALHAKEEM AND MICHAEL SHEVELL
Cognitive enhancers 202
Personal identity and mental impairments 202 Clinical features 269
Identity and enhancement-2 203 Diagnosis 270
Ethical implications for neuroenhancement in persons with Evaluation and testing 271
intellectual disability 204 Microdeletion syndromes 273
Recommendations 205 Monogenetic causes of intellectual disability 274
Conclusion 205 X-linked intellectual disability 275
References 206 Autosomal dominant intellectual disability 275
Autosomal recessive intellectual disability 276
Disease mechanisms 276
16. Genetic counseling Management 277
WENDY R. UHLMANN References 279
Introduction to genetic counseling 209

Components of genetic counseling and case preparation 211 20. Alzheimer’s disease and Down syndrome
Genetic testing 214 KATHRYN L. VAN PELT, ELIZABETH HEAD, FREDERICK A. SCHMITT
Ethical issues 218 AND LISA M. KOEHL
Conclusion 218
References 219 Clinical features 283
Molecular genetics 284
17. Antisense oligonucleotide drugs for neurological Differential diagnosis 287
and neuromuscular disease Current research 289
ROGER M. LANE AND C. FRANK BENNETT Clinical management 290
References 293
Introduction 221
Opportunities for antisense oligonucleotides in neuroscience 221
Mechanisms of action of antisense oligonucleotides 223 21. An overview of Rett syndrome
Chemical modification of antisense oligonucleotides 226 WILLIAM RENTHAL, KRISTEN L. SZABLA AND LISA M. MONTEGGIA
Safety of antisense oligonucleotides 227
Pharmacokinetics/delivery of antisense oligonucleotides 228 Introduction 299
Preclinical studies of antisense oligonucleotides in the central Clinical features 300
nervous system 228 Molecular genetics 301
Clinical development of antisense oligonucleotides 231 Disease mechanisms 302
Patisiran 234 Management 305
Eteplirsen 234 References 306
Conclusion 238 Further reading 309
Disclosure 239
Acknowledgments 239
References 239
22. Fragile X clinical features and neurobiology
M.J. LEIGH AND R.J. HAGERMAN
II Introduction 311
Clinical description 312
Neurologic diseases Genetics and neurobiology 319
Testing 320
Targeted treatments 321
18. Cerebral malformations Behavioral interventions 324
RENZO GUERRINI AND ELENA PARRINI Summary and future perspectives 325
See also 326
Malformations of cortical development 249 Acknowledgments 326
Malformations due to abnormal neuronal migration 255 References 326
x CONTENTS
23. Neurological evaluation and management of Mitochondrial inheritance 391

autism spectrum disorder Segregation and heteroplasmy 393
DNA replication 394
KIMBERLY GOODSPEED, DARRAH HAFFNER, SAILAJA GOLLA,
MARY ANN MORRIS AND PATRICIA EVANS Transcription 396
Translation 396
Introduction 333 Protein importation 398
Diagnosing autism spectrum disorder 333 Acknowledgment 399
Medical evaluation 334 References 399
Etiologies of autism spectrum disorder 336
Pathophysiology of autism spectrum disorder 338
Treatments for autism 339 27. Mitochondrial disorders due to mutations
Conclusion 343 in the mitochondrial genome
References 343 SALVATORE DIMAURO AND VALENTINA EMMANUELE
Introduction 401
24. Angelman syndrome Clinical features 401
JENNIFER M. MATHEWS, EMILY K. COOK, SETH S. MARGOLIS Diagnostic evaluation 404
AND CHARLES A. WILLIAMS Pathology 405
Biochemical findings 407
Summary 349 Molecular genetic findings 408
Clinical features 349 Animal models 410
Molecular genetics 351 Therapy 411
Disease mechanisms 354 Conclusion 411
Cellular and molecular as associated details 355 Acknowledgments 411
Differential diagnosis 356 References 412
Testing 356
Management 356
References 358 28. Mitochondrial disorders due to mutations
in the nuclear genome
PATRICK F. CHINNERY AND RITA HORVATH
25. Prion diseases
JAMES A. MASTRIANNI Clinical overview and history 415
Prevalence 415
Introduction 363
Clinical presentation 415
Origins of discovery 363
Molecular genetics and disease mechanisms 421
Epidemiology 364
Testing 421
Pathologic features of prion diseases 364
Management 422
Genetics of prion diseases 365
References 423
Cellular prion protein biology 366
Prion biology 367
Prion initiation and propagation 369 29. Pyruvate dehydrogenase, pyruvate carboxylase,
Synthesizing prions 370 Krebs cycle, and mitochondrial transport disorders
Prion pathogenesis 370
VIKRAM JAKKAMSETTI, ISAAC MARIN-VALENCIA, QIAN MA
Species barrier 371 AND JUAN M. PASCUAL
Prion strains 372
Prion-related proteins 372 Pyruvate dehydrogenase deficiency 427
Human prion disease phenotypes 373 Pyruvate carboxylase deficiency 430
Diagnostic tests 375 Disorders of the Krebs cycle 432
Therapy 376 Mitochondrial transporter disorders 433
References 377 Acknowledgments 434
References 434
III
Neurometabolic disorders LYSOSOMAL DISORDERS
30. Gaucher disease—neuronopathic forms
RAPHAEL SCHIFFMANN
MITOCHONDRIAL DISORDERS
26. The mitochondrial genome Clinical features 439
ERIC A. SCHON
Natural history and clinical syndromes 440
Typical specific features 441
Mitochondrial origins 389 Auditory dysfunction 441
Genome organization 389 Myoclonus 441
CONTENTS xi
Pathophysiology 442 Differential diagnosis 487
Differential diagnosis 445 Testing 488
References 447 Management 489
Acknowledgments 490
References 490
31. The Niemann Pick diseases
EDWARD H. SCHUCHMAN AND ROBERT J. DESNICK
35. The mucopolysaccharidoses
Introduction 451 DENA MATALON, KIMBERLEE MICHALS MATALON RD
Clinical features and diagnostic evaluation 451 AND REUBEN MATALON
Radiologic and neurophysiologic studies 452
Cellular pathology 452 Introduction 493
Biochemical findings 452 History 493
Brain immunochemical findings 453 Manifestations of the mucopolysaccharidoses 494
Mechanism of disease 453 Therapy for the mucopolysaccharidoses 506
Molecular genetics 453 References 507
Animal models 454 Further reading 511
Therapy 455
Conclusion 457
References 458
36. The mucolipidoses
DENA MATALON, KIMBERLEE MICHALS MATALON RD
AND REUBEN MATALON
32. GM2-gangliosidoses
Introduction 513
GREGORY M. PASTORES AND GUSTAVO H.B. MAEGAWA
Manifestations of the mucolipidoses 513
Brief historical note 461 Sialidosis types I and II 513
Clinical features 462 Biochemical and molecular studies 514
Diagnostic confirmation 464 Galactosialidosis 514
Molecular genetics 464 Biochemical and molecular studies 514
Disease mechanisms 465 Mucolipidosis II (I-cell disease) 514
Imaging 466 Biochemical and molecular studies 515
Differential diagnosis 467 Mucolipidosis III (pseudo-Hurler polydystrophy) 515
Management 467 Biochemical and molecular studies 516
References 469 Mucolipidosis IV 516
Biochemical and molecular studies 516
References 516
33. Metachromatic leukodystrophy and multiple
sulfatase deficiency 37. Disorders of glycoprotein degradation:
FLORIAN S. EICHLER
sialidosis, fucosidosis, α-mannosidosis,
Introduction 473 β-mannosidosis, and aspartylglycosaminuria
Clinical features 474 WILLIAM G. JOHNSON†
Natural history 474
Multiple sulfatase deficiency 475 Introduction 519
Molecular genetics 475 Biosynthesis and biodegradation of glycoproteins 520
Disease mechanisms 476 Sialidosis 521
Differential diagnosis 476 Fucosidosis 525
Testing 476 α-Mannosidosis 527
Management 477 β-Mannosidosis 530
Therapies under investigation 478 Aspartylglycosaminuria 531
34. Krabbe disease: globoid cell leukodystrophy 38. β-Galactosidase deficiency: GM1 gangliosidosis,
DAVID A. WENGER AND PAOLA LUZI Morquio B disease, and galactosialidosis
WILLIAM G. JOHNSON†
Clinical features 481
Molecular genetics 482 Introduction 535
Disease mechanisms 484 GM1 gangliosidosis and Morquio B disease 535
Pathophysiology 485 GM1 gangliosidosis 536
†
Deceased
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xii CONTENTS
Morquio B disease 537 Medical management 582

Galactosialidosis 541 Summary 583
Animal models 544 Acknowledgments 584
Future possibility of therapy 544 References 584
Acknowledgments 544
References 545
43. Schindler disease: deficient α-N-
acetylgalactosaminidase activity
39. Acid ceramidase deficiency: Farber DETLEV SCHINDLER AND ROBERT J. DESNICK
lipogranulomatosis, spinal muscular atrophy
associated with progressive myoclonic epilepsy Introduction 589
and peripheral osteolysis Clinical features and diagnostic results 589
Diagnostic evaluation 593
MICHAEL BECK, HUGO W. MOSER† AND KONRAD SANDHOFF
Pathology 593
Introduction 547 Biochemistry 594
Clinical picture 547 Molecular genetics 595
Diagnosis 550 Relation to other gene loci 596
Pathology 551 Animal model 596
Clinical genetics 553 Therapy 597
Molecular genetics 553 Future research directions 597
Animal models 553 Acknowledgment 597
Therapy 553 References 597
Conclusion and future directions 554
References 555 METAL METABOLISM DISORDERS
44. Wilson disease
40. Wolman disease GOLDER N. WILSON
ISAAC MARIN-VALENCIA AND JUAN M. PASCUAL
Summary 601
Clinical features 559 Clinical features 603
Molecular genetics 559 Natural history 604
Disease mechanisms 560 Molecular genetics 605
Differential diagnosis 561 Disease mechanisms 606
Testing 561 Differential diagnosis 607
Treatment 562 Testing 607
References 564 Management 608
References 610
41. Lysosomal membrane disorders: lysosome-
associated membrane protein-2 deficiency 45. Menkes disease and other ATP7A disorders
(Danon disease) JUAN M. PASCUAL AND JOHN H. MENKES†
KAZUMA SUGIE AND ICHIZO NISHINO
Menkes disease 613
Human muscle disorder due to lysosomal membrane defect 567 Mouse model of Menkes disease 617
Danon disease 567 Occipital horn syndrome 617
Lysosome-associated membrane protein-2 570 ATP7A-related distal motor neuropathy 617
Other autophagic vacuolar myopathies 572 Mode of inheritance of ATP7A related disorders 618
Management 572 Acknowledgments 618
42. Fabry disease: α-galactosidase A deficiency 46. Neurodegeneration with brain iron accumulation
ROBERT J. DESNICK SUSANNE A. SCHNEIDER
Clinical features 575 Introduction and clinical features 621

Mode of inheritance, Incidence, and prevalence 575 Natural history 622
Natural history and clinical manifestations 576 Molecular genetics and genotype phenotype correlations 623
Biochemical genetics 579 Disease mechanisms 625
Molecular genetics 580 Animal models 625
Disease pathology/pathophysiology 581 Investigation 627
Differential diagnosis 582 Differential diagnosis 628
†
Deceased
CONTENTS xiii
Management 628 Genetics of aging and life span 675
References 629 Known genetic variants and longevity 677
Blood-based biomarkers of aging rate 680
Recent developments in longevity research 680
47. Pantothenate kinase associated Conclusion 680
neurodegeneration Acknowledgment 680
SANDRA M.H. NORDLIE, UNA HADZIAHMETOVIC, References 681
SERGIO PADILLA-LOPEZ AND MICHAEL C. KRUER
Introduction 633 51. Vitamins: cobalamin and folate

DAVID WATKINS, CHARLES P. VENDITTI AND DAVID S. ROSENBLATT
Laboratory findings 635
Neuroimaging features 635 Cobalamin 687
Definitive diagnosis 635 Folate 691
Neuropathological findings 636 References 694
Biological basis of disease 637
Current treatment strategies 639
Conclusion and future directions 640 52. Inherited biotin-responsive disorders
References 640 BARRY WOLF
Further reading 641
Biotin 699
Holocarboxylase synthetase deficiency 699
48. Disorders of manganese transport Biotinidase deficiency 702
ISAAC MARIN-VALENCIA AND SIDNEY M GOSPE, JR. Biotin thiamine-responsive basal ganglia disease 706
Other biotin-responsive disorders 707
Introduction 643 Differential diagnosis of the biotin-responsive disorders 707
Physiology of manganese homeostasis 643 Conclusion 707
Disorders of manganese transport resulting in References 708
hypermanganesemia 644
Disorder of manganese transport resulting in manganese
deficiency 645 53. Disorders of pyridoxine metabolism
Molecular genetics 645 CLARA VAN KARNEBEEK, IZABELLA A. PENA AND
Pathophysiology and disease mechanisms 647 SIDNEY M. GOSPE JR.
Differential diagnosis 649
Testing 649 Clinical features 711
Management 651 Historical overview 711
References 652 Mode of inheritance and prevalence 712
Natural history 713
Molecular genetics: antiquitin 714
49. Aceruloplasminemia Molecular genetics: PNPO, TNSALP, and PLPHP 716
YASUSHI HOSOI AND HIROAKI MIYAJIMA Disease mechanisms 716
Pathophysiology 716
Introduction 657 Differential diagnosis 718
Classification 657 Testing 719
Epidemiology 658 Management 720
Clinical manifestations 658 Acknowledgments 724
Neuroimaging 659 References 724
The role of astrocytes in aceruloplasminemia 663
Treatment 664 LIPID METABOLISM DISORDERS
References 666
54. Disorders of lipid metabolism
FRANCO TARONI AND CINZIA GELLERA
VITAMIN DISORDERS
Introduction 731
50. Genetic and dietary influences on life span Pathophysiology 731
YIAN GU, JOSEPH H. LEE AND RICHARD MAYEUX Clinical features 736
Defects of mitochondrial fatty acid oxidation 738
Introduction 671 Other disorders of fatty acid β-oxidation 746
Hypothesis of longevity and senescence 671 Acknowledgments 748
Caloric intake, α-tocopherol, and other dietary factors 673 References 748
xiv CONTENTS
55. Lipoprotein disorders 59. Disorders of galactose metabolism

JOHN P. KANE AND MARY J. MALLOY DIDEM DEMIRBAS AND GERARD T. BERRY

Lipoprotein structure and function 755 Classic galactosemia 803
Lipoprotein and lipid metabolism in the central nervous Uridine diphosphate galactose 4-epimerase deficiency 808
system 757 Galactokinase deficiency 810
Tocopherols 758 Fanconi Bickel syndrome 811
Disorders of lipoproteins containing ApoB 760 Portosystemic venous shunting and hepatic
Disorders of high-density lipoprotein deficiency 762 arteriovenous malformations 811
Conclusion 764 References 811
References 764
60. Inborn errors of amino acid metabolism
phenylketonuria and disorders of
56. Cerebrotendinous xanthomatosis biopterin metabolism
GERALD SALEN AND SHAILENDRA B. PATEL WILLIAM L. NYHAN

Clinical features 767 Classic organic acidemias 818
Molecular genetics 771 Glutaric aciduria type I 820
Disease mechanisms 774 4-Hydroxybutyric aciduria 820
Diagnosis 775 Phenylketonuria and disorders of biopterin metabolism 821
Management 776 Nonketotic hyperglycinemia 822
References 778 Maple syrup urine disease 823
Conclusion and future research directions 824
References 825
OTHER METABOLIC DISORDERS Suggested reading 826
57. Organic acid disorders
MARGRETTA REED SEASHORE
61. Urea cycle disorders
FRANCIS ROSSIGNOL, NICHOLAS AH MEW,
Clinical features 785 MEIRA R. MELTZER AND ANDREA L. GROPMAN
Mode of inheritance and prevalence 786
Introduction 827
Natural history of organic acid disorders 786
Pathophysiology 787
Disease-specific manifestations 830
Genetics and genetic counseling 831
Molecular genetics in diagnosis 788
Testing 789
Expression of urea cycle enzymes and nitrogen metabolism 833
Management 789
Disease mechanisms/pathophysiology 834
Summary 790
References 790
Testing 836
Further reading 790
Management 837
Current research 840
References 840
58. Glycogen and polyglucosan storage
diseases 62. Glucose transporter type I deficiency and
SALVATORE DIMAURO AND HASAN ORHAN AKMAN other glucose flux disorders
JUAN M. PASCUAL
Introduction 793
Clinical features 793 Overview of glucose transport 849
Diagnostic evaluation 797 Clinical features of GLUT1 deficiency 850
Pathology 798 Molecular genetics of GLUT1 deficiency 852
Biochemical findings 798 Disease mechanisms in GLUT1 deficiency 854
Molecular genetic findings 799 Animal models of GLUT1 deficiency 856
Animal models 799 Differential diagnosis of GLUT1 deficiency 857
Therapy 800 Testing for GLUT1 deficiency 857
Conclusion 800 Treatment of GLUT1 deficiency 858
Acknowledgment 800 Acknowledgments 859
CONTENTS xv
63. Maple syrup urine disease: biochemical, 67. Neurotransmitter disorders
clinical and therapeutic considerations ÀNGELS GARCÍA-CAZORLA AND RAFAEL ARTUCH
DAVID T. CHUANG, RODY P. COX AND R. MAX WYNN
Introduction 917
Introduction 865 Disorders of monoamines 918
Clinical presentation of classic maple syrup urine disease 865 References 927
Neuropathology of maple syrup urine disease 866
Variant types of maple syrup urine disease 866
Genetics and prevalence 867
Animal models for classic and intermediate maple syrup 68. Peroxisomal disorders
urine disease 869 GERALD V. RAYMOND
Treatments of classic maple syrup urine disease 871
Domino liver transplantation in maple syrup urine disease 871 Disorders of peroxisome biogenesis 931
Concluding remarks 872 Peroxisomal disorders due to defects in single peroxisomal
Acknowledgments 873 enzymes 935
References 873 Refsum disease 938
Other peroxisomal single enzyme defects 940
References 940
64. Congenital disorders of N-linked glycosylation
MARC C. PATTERSON
Clinical features 877 69. Purines and pyrimidines

Molecular genetics 885 WILLIAM L. NYHAN
Differential diagnosis 886 Hypoxanthine guanine phosphoribosyltransferase
Testing 887 deficiency 943
Management 888 Pathology 945
Conclusion 889 Biochemical findings 945
References 890 Immunochemical findings 946
Molecular and genetic data 946
Animal models of HPRT deficiency 947
65. Disorders of glutathione metabolism Therapy 948
KOJI AOYAMA, CHISATO KINOSHITA AND TOSHIO NAKAKI Conclusion and future research directions 948
Phosphoribosylpyrophosphate synthetase superactivity 948
Glutathione and the γ-glutamyl cycle 897 Clinical features and diagnostic evaluation 949
Disorders of enzymes in the γ-glutamyl cycle 898 Pathology 949
Excitatory amino acid transporters 899 Biochemical findings 949
Disorders of excitatory amino acid carrier 1 leading to Molecular and genetic data 949
glutathione depletion 900 Therapy 949
Neurodegenerative diseases leading to glutathione depletion 900 Therapies under investigation 950
Neurodegenerative diseases and microRNA regulation of References 950
glutathione level 902
Conclusion 904
References 905
70. The acute porphyrias
BRUCE WANG AND D. MONTGOMERY BISSELL
66. Canavan disease
DENA MATALON, KIMBERLEE MICHALS MATALON RD AND Introduction 953
REUBEN MATALON Clinical aspects 955
Diagnosis 957
Introduction 909 Pathogenesis of neurologic symptoms 959
History 909 Inducers of acute attacks 960
Biochemical studies 909 Molecular genetics 962
Clinical features 910 Animal models 962
Diagnosis 910 Treatment 963
Differential diagnosis 911 Liver transplantation 965
Epidemiology 911 Genetic therapy 965
Molecular basis 911 References 965
Prevention/prenatal diagnosis 912
Management 912 Index 971
Therapy 912
References 913
List of contributors
Nicholas Ah Mew Children’s National Medical Center, Philip L. De Jager Department of Neurology, Center for
Washington, DC, United States; The George Washington Translational & Computational Neuroimmunology, Taub
University of the Health Sciences, Washington, DC, Institute for Research on Alzheimer’s Disease and the
United States Aging Brain, Columbia University Irving Medical Center,
Wado Akamatsu Center for Genomic and Regenerative New York, NY, United States
Medicine, Juntendo University School of Medicine, Tokyo, Didem Demirbas Harvard Medical School and Boston
Japan Children’s Hospital, Boston, MA, United States
Hasan Orhan Akman Columbia University Medical Robert J. Desnick Icahn School of Medicine at Mount
Center, New York, NY, United States Sinai, New York, NY, United States
Afnan AlHakeem McGill University Health Centre, Salvatore DiMauro Department of Neurology, Columbia
Montreal, QC, Canada; McGill University, Montreal, QC, University Medical Center, New York, NY, United States
Canada; Prince Sultan Medical City, Riyadh, Saudi Arabia
Florian S. Eichler Massachusetts General Hospital,
Koji Aoyama Department of Pharmacology, Teikyo Harvard Medical School, Boston, MA, United States
University School of Medicine, Tokyo, Japan
Bernice Elger Institute of Biomedical Ethics, University of
Rafael Artuch Sant Joan de Déu Research Institute and Basel, Basel, Switzerland
CIBERER-ISCIII (Centre for Biomedical Research on Rare
Diseases), Barcelona, Spain Valentina Emmanuele Department of Neurology,
Michael Beck Institute of Human Genetics, University of Columbia University Medical Center, New York, NY,
Mainz, Mainz, Germany United States
C. Frank Bennett Ionis Pharmaceuticals, Carlsbad, CA, Patricia Evans Department of Pediatrics, Neurology &
United States Neurotherapeutics, and Psychiatry, University of Texas
Gerard T. Berry Harvard Medical School and Boston Southwestern Medical Center, Dallas, TX, United States
Children’s Hospital, Boston, MA, United States Brent L. Fogel Program in Neurogenetics, Department of
D. Montgomery Bissell University of California San Neurology; Department of Human Genetics; Department
Francisco, San Francisco, CA, United States of Neurology, Clinical Neurogenomics Research Center,
Brenda Canine McLaughlin Research Institute & Great David Geffen School of Medicine, University of
Falls College Montana State University, Great Falls, MT, California, Los Angeles, CA, United States
United States Àngels Garcı́a-Cazorla Sant Joan de Déu Research Institute
C. Thomas Caskey Department of Molecular and Human and CIBERER-ISCIII (Centre for Biomedical Research on
Genetics and Human Genome Sequencing Center, Baylor Rare Diseases), Barcelona, Spain
College of Medicine, Houston, TX, United States Cinzia Gellera Unit of Medical Genetics and
Widler Casy Department of Pediatrics, University of Texas Neurogenetics, Fondazione IRCCS Istituto Neurologico
Southwestern Medical Center, Dallas, TX, United States “Carlo Besta”, Milan, Italy
Patrick F. Chinnery Department of Clinical Neurosciences, Sailaja Golla Department of Pediatrics, Neurology &
University of Cambridge, Cambridge, United Kingdom; Neurotherapeutics, and Psychiatry, University of Texas
MRC Mitochondrial Biology Unit, University of Southwestern Medical Center, Dallas, TX, United States
Cambridge, Cambridge, United Kingdom Kimberly Goodspeed Department of Pediatrics,
David T. Chuang Department of Biochemistry, University Neurology & Neurotherapeutics, and Psychiatry,
of Texas Southwestern, Medical Center, Dallas, TX, University of Texas Southwestern Medical Center, Dallas,
United States; Department of Internal Medicine, TX, United States
University of Texas Southwestern, Medical Center, Dallas, Sidney M. Gospe Jr. Division of Pediatric Neurology,
TX, United States Departments of Neurology and Pediatrics, University of
Emily K. Cook Department of Biological Chemistry, The Washington and Seattle Children’s Hospital, Seattle, WA,
Johns Hopkins University School of Medicine, Baltimore, United States; Department of Pediatrics, Duke University,
MD, United States Durham, NC, United States
Rody P. Cox Department of Internal Medicine, University Steven J. Gray Department of Pediatrics, University of
of Texas Southwestern, Medical Center, Dallas, TX, Texas Southwestern Medical Center, Dallas, TX, United
United States States
xvii
xviii LIST OF CONTRIBUTORS
Andrea L. Gropman Children’s National Medical Center, Chisato Kinoshita Department of Pharmacology, Teikyo
Washington, DC, United States; The George Washington University School of Medicine, Tokyo, Japan
University of the Health Sciences, Washington, DC,
Sanne E. Klompe Department of Biochemistry and
United States
Molecular Biophysics, Columbia University, New York,
Yian Gu Departments of Neurology and Epidemiology, NY, United States
The Taub Institute for Research on Alzheimer’s Disease
and the Aging Brain, The Gertrude H. Sergievsky Center, Lisa M. Koehl Department of Neurology, University of
Columbia University Irving Medical Center, New York, Kentucky, Lexington, KY, United States
NY, United States Michael C. Kruer Molecular & Cellular Biology Program,
Renzo Guerrini Pediatric Neurology Unit and Arizona State University, Tempe, AZ, United States;
Laboratories, Children’s Hospital A. Meyer, University of Departments of Child Health, Neurology, and Cellular &
Florence, Florence, Italy Molecular Medicine, Program in Genetics, University of
Teresa M. Gunn McLaughlin Research Institute, Great Arizona College of Medicine Phoenix, Phoenix, AZ,
Falls, MT, United States United States; Pediatric Movement Disorders Program,
Barrow Neurological Institute at Phoenix Children’s
Una Hadziahmetovic Departments of Child Health,
Hospital, Phoenix, AZ, United States
Neurology, and Cellular & Molecular Medicine, Program
in Genetics, University of Arizona College of Medicine Walter A. Kukull Department of Epidemiology, University
Phoenix, Phoenix, AZ, United States of Washington, Seattle, WA, United States
Darrah Haffner Department of Neurology, Washington Roger M. Lane Ionis Pharmaceuticals, Carlsbad, CA,
University in St Louis, St. Louis, MO, United States United States
R.J. Hagerman University of California at Davis, M.I.N.D.
Institute, Sacramento, CA, United States Joseph H. Lee The Gertrude H. Sergievsky Center,
Columbia University Irving Medical Center, New York,
Tamar Harel Department of Genetic and Metabolic NY, United States
Diseases, Hadassah-Hebrew University Medical Center,
Jerusalem, Israel M.J. Leigh University of California at Davis, M.I.N.D.
Institute, Sacramento, CA, United States
Elizabeth Head Department of Pathology & Laboratory
Medicine, University of California—Irvine, Irvine, CA, Qinglan Ling Department of Pediatrics, University of
United States Texas Southwestern Medical Center, Dallas, TX, United
States
Rita Horvath Department of Clinical Neurosciences,
University of Cambridge, Cambridge, United Kingdom James R. Lupski Department of Molecular and Human
Genetics; Department of Pediatrics, Baylor College of
Yasushi Hosoi First Department of Medicine, Hamamatsu Medicine, Houston, TX, United States; Texas Children’s
University School of Medicine, Hamamatsu, Japan Hospital, Houston, TX, United States
Ying-Chen Claire Hou Human Longevity, Inc., San Diego,
CA, United States Paola Luzi Department of Neurology, Jefferson Medical
College, Philadelphia, PA, United States
Jane Hsiao OPKO Health Inc., Miramar, FL, United States
Hiroyuki Ishiura Department of Neurology, Graduate Qian Ma Department of Neurology and
School of Medicine, The University of Tokyo, Tokyo, Neurotherapeutics, The University of Texas Southwestern
Japan Medical Center, Dallas, TX, United States
Clifford R. Jack Jr. Department of Radiology Mayo Clinic, Gustavo H.B. Maegawa Department of Pediatrics/Genetics
Rochester, MN, United States & Metabolism, University of Florida Gainesville, Florida,
Vikram Jakkamsetti Department of Neurology and United States
Neurotherapeutics, The University of Texas Southwestern Mary J. Malloy University of California, San Francisco
Medical Center, Dallas, TX, United States School of Medicine, San Francisco, CA, United States
William G. Johnson† †(Deceased) Department of Seth S. Margolis Department of Biological Chemistry;
Neurology, Rutgers Robert Wood Johnson Medical Solomon H. Snyder Department of Neuroscience, The
School, New Brunswick, NJ, United States Johns Hopkins University School of Medicine, Baltimore,
Fabrice Jotterand Center for Bioethics and Medical MD, United States
Humanities, Institute for Health & Equality, Medical Isaac Marin-Valencia Laboratory of Developmental
College of Wisconsin, Milwaukee, WI, United States; Neurobiology, The Rockefeller University, New York, NY,
Institute of Biomedical Ethics, University of Basel, Basel, United States
Switzerland
James A. Mastrianni Department of Neurology, Center for
John P. Kane University of California, San Francisco School Comprehensive Care and Research on Memory Disorders,
of Medicine, San Francisco, CA, United States Helen McLoraine Neuroscientist of the Brain Research
Olga Khorkova OPKO Health Inc., Miramar, FL, United Foundation, The University of Chicago, Chicago, IL,
States United States
LIST OF CONTRIBUTORS xix
Dena Matalon Stanford University, Stanford, CA, United William L. Nyhan Professor of Pediatrics, University of
States; The University of Houston, Houston, TX, United California, La Jolla, CA, United States; Department of
States; The University of Texas Medical Branch, Pediatrics, University of California San Diego, San Diego,
Galveston, TX, United States CA, United States
Reuben Matalon Stanford University, Stanford, CA, United Hideyuki Okano Department of Physiology, Keio
States; The University of Houston, Houston, TX, United University School of Medicine, Tokyo, Japan
States; The University of Texas Medical Branch, Sergio Padilla-Lopez Departments of Child Health,
Galveston, TX, United States Neurology, and Cellular & Molecular Medicine, Program
in Genetics, University of Arizona College of Medicine
Kimberlee Michals Matalon Rd Stanford University,
Phoenix, Phoenix, AZ, United States
Stanford, CA, United States; The University of Houston,
Houston, TX, United States; The University of Texas Elena Parrini Pediatric Neurology Unit and Laboratories,
Medical Branch, Galveston, TX, United States Children’s Hospital A. Meyer, University of Florence,
Florence, Italy
Jennifer M. Mathews Division of Pediatric Genetics and
Metabolism, University of North Carolina, Chapel Hill, Juan M. Pascual Department of Neurology
NC, United States and Neurotherapeutics; Department of Physiology;
Department of Pediatrics; Eugene McDermott Center for
Richard Mayeux Department of Neurology and the Taub
Human Growth & Development/Center for Human
Institute for Research on Alzheimer’s Disease and the
Genetics; Division of Pediatric Neurology; The University
Aging Brain, Columbia University Irving Medical Center,
of Texas Southwestern Medical Center, Dallas, TX,
New York, NY, United States
United States
Jennifer McCurdy University of Alaska Anchorage,
Gregory M. Pastores National Centre for Inherited
Anchorage, AK, United States
Metabolic Disorders, Mater Misericordiae University
Meira R. Meltzer Children’s National Medical Center, Hospital, University College Dublin, Dublin, Ireland
Washington, DC, United States; The George Washington
Shailendra B. Patel University of Cincinnati College of
University of the Health Sciences, Washington, DC,
Medicine, Cincinnati, OH, United States
United States
† Marc C. Patterson Mayo Clinic, Rochester, MN, United
John H. Menkes† (Deceased)
States
Justin Miron Centre for Studies in the Prevention of
Izabella A. Pena Department of Biology, Whitehead
Alzheimer’s Disease, Douglas Mental Health University
Institute for Biomedical Research, Massachusetts Institute
Institute, Verdun, QC, Canada
of Technology, Cambridge, MA, United States
Jun Mitsui Department of Neurology, Graduate School of
Cynthia Picard Centre for Studies in the Prevention of
Medicine, The University of Tokyo, Tokyo, Japan
Hiroaki Miyajima First Department of Medicine, Institute, Verdun, QC, Canada
Hamamatsu University School of Medicine, Hamamatsu,
Judes Poirier Centre for Studies in the Prevention of
Japan
Lisa M. Monteggia Vanderbilt Brain Institute, Vanderbilt Institute, Verdun, QC, Canada
University, Nashville, TN, United States
Jennifer E. Posey Department of Molecular and Human
Mary Ann Morris Children’s Health Dallas, Dallas, TX, Genetics and Human Genome Sequencing Center, Baylor
United States College of Medicine, Houston, TX, United States
Hugo W. Moser† †(Deceased) Kennedy Krieger Institute, Gerald V. Raymond Pediatric Neurology, Department of
Johns Hopkins University, Baltimore, MD, United States Pediatrics and Neurology, Penn State Children’s Hospital,
Melissa E. Murray Department of Neuroscience, Hershey, PA, United States
Jacksonville, FL, United States William Renthal Department of Neurology, Brigham and
Toshio Nakaki Department of Pharmacology, Teikyo Women’s Hospital, Harvard Medical School, Boston, MA,
University School of Medicine, Tokyo, Japan United States
Nathalie Nilsson Centre for Studies in the Prevention of David S. Rosenblatt Departments of Human Genetics,
Alzheimer’s Disease, Douglas Mental Health University Medicine, Pediatrics and Biology, McGill University,
Institute, Verdun, QC, Canada Montreal, QC, Canada
Francis Rossignol Children’s National Medical Center,
Ichizo Nishino Department of Neuromuscular Research,
Washington, DC, United States; National Institutes of
National Institute of Neuroscience, National Center of
Health, Bethesda, MD, United States
Neurology and Psychiatry (NCNP), Tokyo, Japan
Gerald Salen Rutgers New Jersey Medical School, Newark,
Sandra M.H. Nordlie Molecular & Cellular Biology Program, NJ, United States
Arizona State University, Tempe, AZ, United States
Konrad Sandhoff LIMES Institute, Kekulé-Institute,
Robert L. Nussbaum Invitae Corporation, San Francisco, University of Bonn, Bonn, Germany
CA, United States
xx LIST OF CONTRIBUTORS
Raphael Schiffmann Baylor Scott & White Research Wendy R. Uhlmann Division of Genetic Medicine,
Institute, Dallas, TX, United States Department of Internal Medicine and Human Genetics,
Detlev Schindler University of Würzburg, Würzburg, University of Michigan Medical School, Ann Arbor, MI,
Germany United States
Frederick A. Schmitt Departments of Neurology, Clara van Karnebeek Department of Pediatrics, Amalia
Neurosurgery, Psychiatry, Psychology, Behavioral Children’s Hospital, Radboud University Medical Centre,
Science, Sander’s Brown Center on Aging, Spinal Cord Nijmegen, The Netherlands; Department of Pediatrics,
and Brain Injury Research Center, University of Kentucky, Emma Children’s Hospital, Amsterdam University
Lexington, KY, United States Medical Centres, Amsterdam, The Netherlands
Susanne A. Schneider Department of Neurology, Ludwig- Kathryn L. Van Pelt Sanders-Brown Center on Aging,
Maximilians-University Munich, Munich, Germany University of Kentucky, Lexington, KY, United States
Eric A. Schon Departments of Neurology and of Genetics Prashanthi Vemuri Department of Radiology Mayo Clinic,
and Development, Columbia University, New York, NY, Rochester, MN, United States
United States Charles P. Venditti Organic Acid Research Section,
Edward H. Schuchman Icahn School of Medicine at Mount National Human Genome Research Institute, National
Sinai, New York, NY, United States Institutes of Health, Bethesda, MD, United States
Margretta Reed Seashore Genetics, Yale School of Claes Wahlestedt Center for Therapeutic Innovation and
Medicine, New Haven, CT, United States the Department of Psychiatry and Behavioral Sciences,
University of Miami Miller School of Medicine, Miami,
Frances C. Shaffo Department of Pediatrics, University of
FL, United States
Texas Southwestern Medical Center, Dallas, TX, United
States Bruce Wang University of California San Francisco, San
Francisco, CA, United States
Michael Shevell McGill University Health Centre,
Montreal, QC, Canada; McGill University, Montreal, QC, David Watkins Department of Human Genetics, McGill
Canada University, Montreal, QC, Canada
Sarah E. Sinnett Department of Pediatrics, University of David A. Wenger Department of Neurology, Jefferson
Texas Southwestern Medical Center, Dallas, TX, United Medical College, Philadelphia, PA, United States
States Charles A. Williams Division of Genetics and Metabolism,
Myriam Srour McGill University Health Centre, Montreal, Department of Pediatrics, University of Florida School of
QC, Canada; McGill University, Montreal, QC, Canada Medicine, Gainesville, FL, United States
Samuel H. Sternberg Department of Biochemistry and Golder N. Wilson Pediatrics, Texas Tech University Health
Molecular Biophysics, Columbia University, New York, Science Center, Lubbock, TX, United States;
NY, United States KinderGenome Medical Genetics, Dallas, TX, United
States
Kazuma Sugie Department of Neurology, Nara Medical
University School of Medicine, Kashihara, Japan Barry Wolf Division of Genetics, Birth Defects and
Metabolism, Department of Pediatrics, Ann and Robert H.
Kristen L. Szabla Vanderbilt Brain Institute, Vanderbilt
Lurie Children’s Hospital of Chicago and Northwestern
University, Nashville, TN, United States
University Feinberg School of Medicine, Chicago, IL,
Franco Taroni Unit of Medical Genetics and Neurogenetics, United States
Fondazione IRCCS Istituto Neurologico “Carlo Besta”,
R. Max Wynn Department of Biochemistry; Department of
Milan, Italy
Internal Medicine, University of Texas Southwestern,
Marina Tedeschi Dauar Centre for Studies in the Medical Center, Dallas, TX, United States
Prevention of Alzheimer’s Disease, Douglas Mental
Hung-Chun Yu Human Longevity, Inc., San Diego, CA,
Health University Institute, Verdun, QC, Canada
United States
Shoji Tsuji Department of Neurology, Graduate School of
Medicine, The University of Tokyo, Tokyo, Japan
Foreword
Thirty-seven years ago, I was a resident in the Department of Neurology at UT Southwestern, chaired by R.N.
Rosenberg, always a splendid teacher and now a coeditor of this book. I was intent on learning more about neu-
rology because I was eager to engage with the profound mysteries the brain presented. Disorders of higher corti-
cal function, bearing both on consciousness and on its content, were particularly fascinating to me at the time.
What a magnificent scientific frontier to explore!
It was of course a different world in those days. The causes of inherited metabolic diseases of the nervous sys-
tem had in some instances been determined through biochemical studies. But most genetic diseases of the ner-
vous system remained elusive. What caused Huntington’s disease? Spinocerebellar ataxia? Wilson’s disease?
Amyotrophic lateral sclerosis? Limited progress and much guesswork seemed to prevail in 1982.
Within a few years, many of these mysteries had been swept away. Positional cloning, sometimes carried out
in humans and sometimes in mice, had unambiguously solved many of the Mendelian disorders. Although I had
taken a different direction in science by that time (using genetics to study immunity), I never lost my early inter-
est in the brain. It was a pleasure to witness the discovery of mutations responsible for classical diseases.
Sometimes, it seemed, the causes of two or three such diseases would be published within the space of a week. It
was the beginning of a golden age, yet revolution has yet to run its course. In time, we all came to realize that
some disease phenotypes result from multiple genetic causes. Not all of the relevant genes have yet been discov-
ered. Some diseases are complex rather than Mendelian; some are epigenetic rather than genetic. Nonetheless,
progress has exceeded what anyone might have forecast in the early 1980s.
Solving Mendelian disorders was once a difficult task. Many years were devoted to confining a causative mutation
to a critical region; then to finding the gene content of the region; finally to finding the causative mutation itself. The
sequence of the human and mouse genomes led to the present situation in which there are no longer “new” genes for
which one must search. Advances in engineering and chemistry led to massively parallel sequencing platforms that
simplified mutation finding. Today, at least in the mouse, we have reached a point where induced germline mutations
are found in real time (as quickly as a phenotype is detected, its cause is known). Although it has not been our primary
pursuit, my colleagues and I have made quite a number of interesting neurobehavioral phenotypes in mice using a
germline mutagen. We have, in some instances, shed light on orthologous human diseases. Complex diseases remain
difficult to solve, but one may at least see ways to deal with the problem.
Anyone who has absorbed the chapters of this book will understand that it is not enough to create or discover
an interesting phenotype and know its genetic cause. A long road lies beyond that achievement. One must grasp
the mechanism by which the mutation causes the phenotype, and often this requires a great effort. A “combined
arms” doctrine may be used, in the hope that the best tools of structural biology, biochemistry, and cell biology
will yield mechanism.
The word “mechanism” is itself a bit vague. Do we mean understanding in terms of cellular or subcellular
processes? The atomic level? Far less than that? Mechanistic understanding puts us in mind of machines: devices
we create and therefore understand as well as we might understand anything. Most of us accept that we are bio-
logical machines. But biological machines are unique in their ability to be self-aware, and to experience joy, rage,
fear, desire, and grief. Machines of our own construction, though capable of emulating thought by virtue of exe-
cuting binary programs, actually possess no ability to think nor any of the other attributes just named. We have
come to know many of the molecules of the nervous system needed for its normal function. We have come to
understand how some of these molecules operate. Yet, where mechanism is concerned, a wide gulf still separates
us from understanding just how mentation comes about. Accordingly, my fascination with disorders of higher
cortical function has not faded. Neuroscience remains every bit the alluring frontier it was 37 years ago, or 100
years ago, or 4000 years ago, notwithstanding that the heart was held responsible for thought at that time.
Bruce Beutler
Nobel Laureate, University of Texas Southwestern Medical Center,
Dallas, TX, United States
xxi
Prologue
This is a momentous time in basic and translational neuroscience. The field is buzzing with new results, and
more findings especially on the role of circuits in behaviors are announced on a daily basis. As described next,
four methodological developments in particular have transformed neuroscience over the last decade, producing
several major conclusions that are broadly illustrated in many of the excellent chapters of this book.
First, approaches using large datasets that are based on unbiased surveys of a sample—a cell, a brain region,
or a person—with new large-scale techniques, such as exome sequencing, transcriptome analyses by RNAseq, or
proteomics. These approaches have yielded a plethora of data, the interpretation of which is often facilitated by
sophisticated statistical approaches. Among others, these large datasets have demonstrated that individual neu-
rons can be classified into groups and types but nevertheless display large variations in gene expression, suggest-
ing that even neurons of the same type can exhibit a range of functional properties. As another example, these
datasets have revealed an enormous degree of plasticity in gene expression and protein states, demonstrating
that even at the level of individual cells (such as a neuron), no state is constant.
Second, the systematic analysis of patient populations by genetic methods such as microarray analyses, exome
sequencing, and whole-genome sequencing has revolutionized our view of the human genome and of its role in
neuropsychiatric disorders. Specifically, we now know that the human genome is extraordinarily fluid and
undergoes dramatic changes from one generation to the next, changes that are often associated with diseases.
Moreover, these analyses have identified many new disease associations of genes that were previously not linked
to any neuropsychiatric disorder. Thus the term “genetic disease” has changed: a disorder such as schizophrenia
can be both genetically conditioned and also be noninherited because the predisposing mutation happened de
novo in the germ line, that is, was inherited from a parent who did not actually carry the same mutation in her
or his brain. Moreover, we now realize that especially neuropsychiatric disorders are not strongly influenced by
a few genes but can probably be promoted by mutations in hundreds of genes. These diseases are neither poly-
genic nor Mendelian in nature; instead, partial dysfunctions of neurons and circuits induced by a large number
of different genetic changes can predispose to these diseases. Furthermore, many genes are associated with multi-
ple disorders; for example, NRXN1 deletions are among the more frequent single-gene mutations associated with
a range of neurodevelopmental diseases, including schizophrenia, autism, and Tourette syndrome. These insights
have profound implications about how we think about the human brain and its disorders, as illustrated in the
chapters of this book.
Third, innovative techniques for controlling neuronal activity by light or drugs and new methods for mapping
connections between neurons have produced an avalanche of information on “circuits,” resulting in what could
almost be described as an industry of circuit neuroscientists who probe the role of particular classes of neurons
and their connections in specific behaviors. These new approaches of circuit neuroscience, richly supported by
NIH via the brain project, have motivated thousands of neuroscientists to participate in the effort of mapping
brain circuits and testing the involvement of specific types of neurons in behaviors. The term “circuit” continues
to be ambiguous since it is generally meant to describe a chain of neurons connected by synapses, not a particu-
lar computational arrangement of synapses linking neurons into a functional unit. Nevertheless, “circuit neuro-
science” has come to dominate neuroscience over the last decade. The data emerging from these studies, again as
described in several chapters of this book, are informative about the design of the brain and have the potential to
reshape our view of how the brain works.
Fourth, at the opposite extreme of the methodological scale from circuit neuroscience, cryo-electron micros-
copy has dramatically changed the study of large molecular entities that govern cellular functions, such as the
excitation of neurons. Whereas, traditionally, an atomic description of, for example, an ion channel or a ribosome
required painstaking attempts at producing protein crystals and solving their structures, cryo-electron micros-
copy has enabled a description of the atomic structure of large molecules without the need for crystals. This
advance allows not only faster analysis of large protein complexes but also more rapid studies of molecular
xxiii
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xxiv Prologue
assemblies that previously escaped crystallization. The short-term impact of cryo-electron microscopy on neuro-
science has not been as obvious as that of the other methodological advances described previously, but its long-
term importance cannot be overestimated. In the end a neuron’s role in a circuit or brain will not be understood
without deconvolution of the signaling events in that neuron itself. After all, action potential spikes are unlikely
by themselves to describe the function of a neuron in a circuit or brain, and the signaling events in a neuron
depend on its macromolecular complexes. Understanding such signaling events requires the atomic resolution of
the roles of a neuron’s macromolecular signaling machines, not only of its ion channels and neurotransmitter
receptors, but also, and arguably more importantly, of its intracellular molecular assemblies that amplify and
channel signals. Cryo-electron microscopy will be a key contributor to our understanding of how the cells of the
brain, both the neurons and glia, function as signaling units.
The current book presents, in a Herculean effort, an attempt to communicate our current understanding of the
molecular and genetic basis of brain disorders. In 113 chapters written by experts in the field, the book provides
an overview of this very important area of neuroscience. It is a much needed effort because neuroscience has
become balkanized, divided into fiefdoms that are often separated by cognitive walls. By compiling chapters
illustrating different approaches and subjects, the current book enables neuroscientists to achieve a more integra-
tive view of translational neurobiology and facilitates further studies on that most magical of all organs that is
the brain. Moreover, the book not only focuses on the most exciting recent developments in neuroscience that
have dramatically advanced our understanding of the brain as described earlier, but also it includes vast areas of
more traditional neuroscience that are in danger of being forgotten, such as electrophysiology and cell biology.
These areas obviously continue to be essential for our future understanding of the brain both in order to integrate
various approaches and to form the basis for an understanding of disease processes. Here, too, the book makes a
valuable contribution of general relevance to scientists in the field, setting the stage for the next major develop-
ment in translational neurobiology: a comprehensive understanding that goes beyond circuits and atomic
structures!
Thomas C. Südhof
Nobel Laureate, Stanford University, Stanford, CA, United States
Introduction
We are publishing the sixth edition of “Rosenberg’s Molecular and Genetic Basis of Neurologic and Psychiatric
Disease.” The first edition appeared in 1993 followed by editions in 1997, 2003, 2008, and 2015. We are most grate-
ful for the foresight, dedication, and authorship of our former editors for the success of the first five editions. They
are Stanley B. Prusiner, Salvatore DiMauro, Robert L. Barchi, Louis M. Kunkel, Henry L. Paulson, Louis Ptacek,
and Eric J. Nestler. The sixth edition is edited by Roger N. Rosenberg and Juan M. Pascual.
This edition has been expanded and now includes chapters on Precision Medicine, Genomics, Epigenomics,
Immunogenetics, CRISPR Therapy, Antisense Oligonucleotide Drugs, Rett Syndrome, DNA Sequencing and
other methods of exonic and genomic analysis; Pharmacogenomics, Causation, association and other statistical
tools, Stem Cells and Therapeutic Development, Neuroimaging, Genetic Counseling, Neurodegeneration with
Brain Iron Accumulation, Pantothenate Kinase Deficiency, Disorders of Manganese Transport,
Aceruloplasminemia, Congenital Disorders of Nlinked Glycosylation. Neurotransmitter Disorders,
Frontotemporal Dementias, Dystonia, Glioblastoma, Tuberous Sclerosis, Von Hippel Lindau Disease,
Incontinentia Pigmenti, Vanishing White Matter Disease, Pain Disorders, Stroke, Sickle Cell Disease, and Autism.
Clearly, neurogenetics and neurogenomics have advanced rapidly and are now poised to develop in the next
decade effective targeted neurotherapeutics.
In the 27 years spanning the six editions of our book, molecular genomic analyses of the human genome have
been implemented seeking the genetic basis for natural selection providing biological fitness and also risk of
developing disease. Genome-wide association studies (GWAS) seeking gene variations, single nucleotide poly-
morphisms (SNPs), causal of several human diseases have been conducted in recent years, including autism,
schizophrenia, obesity, diabetes, and heart disease.
Whole-genome sequence (WGS) studies, whole-exome sequence (WES) studies, and GWAS for association or
causation with neurological diseases have been reported extensively in the past decade. An increased risk or cau-
sation for amyotrophic lateral sclerosis, Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis, epi-
lepsy, restless leg syndrome, and several movement disorders has been associated with polymorphisms or
mutations in specific genes. These observations have advanced an understanding of the causation of inherited,
complex polygenetic, multifactorial neurological diseases. They have been made possible by the publication of
the human genome and haplotype studies (HapMap analyses).
The hope with neurome-wide association studies has been that the complete complement of variant genes will be
identified causal of the major neurodegenerative diseases. Then, pharmaconeuromic therapy would not be far behind.
WES and WGS have provided new and important data of the major genes responsible for major human traits and
common diseases. WES and WGS have provided insights into gene variations in low-penetrant genes causal for poly-
genetic, multifactorial neurological disease, as AD. Overall, about 400 genetic variants have been identified that con-
tribute to human traits and diseases, including neurological diseases, and increasing numbers of specific mutations
causal of neurological diseases have been documented in recent years. The momentum is increasing and is highly pos-
itive leading to potential therapies with gene editing using the CRISPR CAS9 editing system.
Sequencing candidate genes for disease, including their surrounding regions in thousands of people, will be
needed to discover more associations with disease. SNPs are turning out not to be a stringent enough level of anal-
ysis seeking genetic risks for disease. Analyses of common, low-penetrance variants causal of common diseases
along with rare low- or moderately penetrance variants are being extensively analyzed with WES and WGS. It is
now necessary to move beyond sequencing candidate genes and surrounding regions for disease association and
provide whole genome or WESs to find the missing heritability. Francis Collins, Director of the National Institutes
of Health, has suggested that the 1000 genomes project, designed to sequence the genomes of at least 1000 people
from all over the world, would provide a powerful approach to finding the hidden heritability.
The BRAIN Initiative to determine the connectome of the human brain proposed by President Obama is now
well underway and is expected to grow into a major scientific endeavor comparable to the Human Genome
Project. It is intended to develop new technologies to identify, define, and decode the neuronal circuitry required
for the storage and retrieval of digital information for specific brain activities, including cognition, and then pro-
vides the basis for altered information transfer in neurologic and psychiatric diseases.
xxv
xxvi Introduction
The genetic explanations that would be of primary interest to find the missing heritability for genetic neuro-
logical disease missed by GWAS include copy-number variation (CNV), epistatic effects, and epigenetics. CNV
refers to regions of DNA that are up to hundreds of base pairs long that are deleted or duplicated between indi-
viduals. There are strong CNV associations between schizophrenics compared to normals and they may arise de
novo in persons without a family history of the mutation. Epistasis, where one or more modifying genes reduce
or enhance the effect of another gene, may be an important genetic mechanism at work to explain heritability.
Epigenetics is another vital area to be explored. It refers to changes in gene expression that are inherited but not
caused by alteration in the sequence of the gene. We now know that gene expression is altered by methylation or
acetylation of CpG and adenine regions of DNA and by methylation of specific histone proteins and also by inhi-
bition of messenger RNA expression by iRNA or microRNA binding.
The 21,000 protein-coding genes in the human genome make up less than 1.2% of the human genome.
Analysis of the remaining 98.8% of the human genome and its role in the causation of human neurological dis-
eases, both inherited and acquired, is a formidable challenge yet unexplored to any degree. RNA transcripts and
their effects on regulation and levels of gene expression is one of the next frontiers for neuromics.
Then, there is the issue that natural selection only functions before or during the reproductive years and not
afterward, when AD and Parkinson’s disease occur. Natural selection has as its major biological function to select
for fitness allowing for reproduction and maintenance of a lineage or species. Aging and neurodegenerative dis-
eases seem to have escaped the forces of natural selection by occurring after the reproductive years. On the other
hand, perhaps evolution has actually selected for aging and neurodegenerative diseases as a means to maintain
the limits of a finite lifespan.
Clearly, neuromics must address the molecular basis of brain aging and why the aging process provides a per-
missive environment to allow the opportunistic neuromic program causal of late-onset neurodegenerative dis-
eases to be expressed.
The cause of AD is due both to genetic polymorphisms and specific mutations (PS1, Ps2, and APP genes) and
environmental stimuli. In this view, environmental stimuli, to be determined, influence the production of an
abnormal pattern of gene expression causal of AD. So, we will have to understand the process of natural selec-
tion in the context of the selection pressures from the environments that we inhabit. Darwin emphasized adapta-
tion to a changing environment as the principal selective influence for evolution. This principle is valid studying
the interaction of environmental stimuli and the genetic factors causal of neurodegenerative diseases.
Deriving induced pluripotent stem cells from late-onset AD patients and differentiating them into neuroblasts
would be one way to screen compounds to see if an abnormal pattern of gene expression is produced compared
to derived neuroblasts from normal controls. Here would be a method to link environment to the genetic pro-
gram causal of AD. It would also be a means to screen potential therapeutic agents that correct an abnormal pat-
tern of gene expression seen in AD patients as a prelude to a clinical trial.
The 200 years since Darwin’s birth, 150 years since the publication of Origin of Species, and the 27 years of the
publication of the six editions of this book is a brief time in human experience. The sixth edition builds on the
development of neurogenetics, genomics/neuromics, and epigenomics during the past 30 years and documents
the advances in genome sequencing, CNV, epistasis, epigenetics, RNA regulation of gene expression, and stem
cell applications to decipher how mutations in these genetic functions are causal of neurological diseases.
Recent significant progress includes effective therapy for patients with spinal muscular atrophy (SMA) using
adeno-associated virus as the vector for the survival motor neuron (SMN)1 gene and also utilizing antisense-
oligonucleotides for SMN2 gene that modulates premessenger RNA splicing of the SMN2 gene achieving suffi-
cient SMN2 gene expression for SMA patients to acquire independent walking at 3 years of age. Of great practi-
cal clinical importance, in addition, it is now possible to determine the gene mutation in over 30% of patients
with inherited neuromuscular disease utilizing WES.
We look forward to future editions of this book documenting the clinical and molecular bases of inherited neu-
rological and psychiatric diseases and associated therapeutics and wish to express our gratitude to our many
loyal colleagues who have participated in all the six editions and thank our new authors for their contributions
to maintain the book’s scientific rigor and excellence. We note with sadness and gratitude the death of our
esteemed colleague, William G. Johnson, who was an author in all six editions of our book. His chapters on
“Beta-Galactosidase Deficiency: GM1 Gangliosidosis, Morquio B Disease, and Galactosialidosis” and “Disorders
of Glycoprotein Degradation: Sialidosis, Fucosidosis, alpha-Mannosidosis, beta-Mannosidosis and
Aspartylglycosaminuria” express fully his immense scholarship and scientific contributions. He was a great
molecular geneticist and we mourn his loss. Our special gratitude is extended to our Project Managers Kristi
Anderson, Melanie Tucker and Sujatha Thirugnana Sambandam for their foresight, insights, efforts, and support
to publish this edition efficiently, effectively, and on time. We are indebted to you.
Roger N. Rosenberg and Juan M. Pascual
Editors
C H A P T E R
1
Mendelian, non-Mendelian, multigenic
inheritance, and epigenetics
Tamar Harel1 and James R. Lupski2,3,4
1
Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
2
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
3
Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States 4Texas Children’s Hospital,
Houston, TX, United States
Introduction
More than 80% of genes are expressed in brain.1 This explains why variation in countless genes and biological
pathways affect neurological phenotypes. The impact of genetics on neurological disease ranges from strict
Mendelian inheritance, wherein a pathogenic variant in a single disease-causing gene or locus results in a
predictable disease phenotype, to multifactorial inheritance, where a complex trait is determined by a combina-
tion of various genetic and nongenetic susceptibility factors. Between these extremes is a continuum of genetic
influence on disease pathophysiology. Mendelian disease traits represent the most basic and simple pattern of
inheritance: variants in disease-associated genes result in specific observable inheritance patterns in families (ver-
tical autosomal dominant, AD; horizontal or autosomal recessive, AR; diagonal X-linked, XL; maternal, mitochon-
drial) often dictated by the molecular consequence of the variant at the locus. Non-Mendelian traits reveal some
complexity in their mode of inheritance, often due to epigenetic factors associated with disease mechanisms.
Oligogenic inheritance involves interaction between two or more genes in disease manifestation. Complex traits can
involve multiple genes as susceptibility or protective factors, that lead to disease when combined with other
intrinsic (e.g., comorbid health conditions) and extrinsic (e.g., environment, lifestyle, diet, infection, drug expo-
sure) factors.
Regardless of the mode of inheritance, defining specific genetic factors that are associated with certain diseases
and their functional role in phenotypic manifestations is important for patient diagnosis, patient management
and genetic counseling in families, as well as for understanding disease mechanisms at the molecular level and
ultimately developing new therapeutic approaches. In this chapter, we review the modes of inheritance that can
be observed in various human neurologic and psychiatric diseases, and how genetics and more recently geno-
mics is increasing our molecular understanding of neurological disease.
Mendelian traits
Mendel’s laws
The basic rules of inheritance were established by Gregor Mendel, based upon his observation of the segregation
of traits (i.e., phenotypes that segregated in specific patterns or ratios during transmission from parents to off-
spring) in the common garden pea.2 Mendel’s first law, the principle of independent segregation, referred to as the
ability of genes, which he called factors, to segregate independently during the formation of gametes or sex cells.
Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease.

DOI: https://doi.org/10.1016/B978-0-12-813955-4.00001-5 3 © 2020 Elsevier Inc. All rights reserved.
4 1. Mendelian, non-Mendelian, multigenic inheritance, and epigenetics
Mendel’s second law, the principle of independent assortment, was derived from his observations using peas that
differed by more than one characteristic or trait. Mendel postulated that only one factor from each pair was inde-
pendently transmitted to the gamete during sex-cell formation and that any one gamete contains only one type of
inherited factor from each pair. There is no tendency for genes arising from one parent to stay together. Of course,
we now know that this latter principle is true only for unlinked genes. Genes or loci that are linked, or physically
located in close proximity on the same chromosome, do not assort independently. The closer these loci are, the
more frequently they will cosegregate and it is this principle that is the basis of genetic linkage mapping.
Chromosomes and genes

The chromosomal theory of heredity expounded by Walter Sutton emphasized that the diploid chromosome
group consists of a morphologically similar set, a homologous pair, for each chromosome and that during meio-
sis every gamete receives only one chromosome of each homologous pair. This observation was used to explain
Mendel’s results by assuming that genes, or factors, were part of the chromosome. Genes are arranged in a linear
order on the chromosome, each having a specific map position or locus. There are two copies for each gene at a
given locus, one on each chromosome homologue. These two copies, or alleles, may be identical (homozygous)
or different (heterozygous) at a specific autosomal locus. When only one copy is physically present, either
because of deletion of a specific genomic region on the other homologue or because of the special circumstances
of the X-chromosome in 46,XY males, this condition is referred to as hemizygous. The genes are passed to the next
generation through parental gametes, which contain only one of the two alternative gene copies. A particular
gamete may contain alleles from different chromosome homologues because of chromosome crossover and
recombination of alleles that occur during meiosis.
Mendelian inheritance
Mendelian traits are determined by a single gene or locus. Pathogenic variants at such loci result in diseases
that follow Mendel’s laws of segregation and independent assortment. The three major patterns of Mendelian
inheritance are AD, AR, and XL (Fig. 1.1). Mendelian inheritance patterns refer to observable traits and not to
genes. Thus some alleles at a specific locus may lead to traits that segregate in a dominant manner, whereas other
alleles at the same locus may segregate in a recessive manner.
AD alleles exert their effect despite the presence of a corresponding normal allele on the homologous chromo-
some. A vertical transmission pattern is observed in the pedigree, with the trait manifested in approximately half
of the individuals in each generation (Fig. 1.1A). An affected individual will have a 50% chance of transmitting
the disease to each independent offspring, which is a reflection of whether a mutant or a normal allele is segre-
gated in the gamete involved in fertilization. Reduced penetrance is sometimes observed with AD traits, whereby
individuals with the mutant allele do not manifest disease.
In AR inheritance, both alleles must be abnormal for the disease trait to be expressed. The unaffected parents
of an affected child are obligate heterozygote carriers for the recessive mutant allele. Affected children may be
homozygous for a specific recessive mutant allele, as is more commonly observed with consanguineous matings,
or they may be compound heterozygotes for two different alleles. Couples who are heterozygous carriers of a
recessive mutant allele have a 25% risk of having an affected child with each pregnancy. The pattern of transmis-
sion observed in the pedigree is horizontal, with multiple members of one generation affected (Fig. 1.1B).
Unaffected siblings of an affected individual have a 67% (two-thirds) chance of being a carrier for the mutant
allele.
X-linked inheritance patterns reflect special circumstances regarding sex chromosomes. Females have two
X-chromosomes, while males have one X-chromosome and one Y-chromosome. In X-linked recessive inheritance,
a mutation in a gene located on the X-chromosome may not express itself in females because of the normal copy
on the other X-chromosome. However, all males who inherit the mutant allele will be affected. An important fea-
ture of X-linked inheritance is that male-to-male transmission never occurs because the father contributes the
Y-chromosome and not the X-chromosome to his sons. However, all female offspring of affected males inherit
the abnormal allele. Therefore affected fathers will have genetically normal sons and obligate carrier daughters
(Fig. 1.1C).
X-linked recessive disorders may sometimes manifest in females because of a skewing in the process of lyoniza-
tion or X-inactivation. Under normal circumstances, the expression of one of the two X-chromosomes in females
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his father-in-law was still alive. He wished to reign over the Holy
Land, but he liked the ease of his court too well to be in haste to
fight. He had friends, too, amongst the Saracens, so though the
Pope bade him set forth on the Crusade, he always found an excuse
for delay. At last he did sail, but he became ill and landed again in
three days.
The Pope was so angry that he preached against him. He said
that the illness was not real.
The clergy and the Pope stood round the altar in the great
cathedral at Rome. The bells clanged above. Each man except the
Pope carried a lighted torch. After the Pope had spoken of all the
wrong things the emperor had done he paused. Then in the dim
light he prayed that God would curse Frederick. As he prayed, the
clergy lowered the torches and dashed out their flames against the
stone floor to show the darkness in which they wished that
Frederick’s soul might be.
All this was told to Frederick. He was terribly angry. He had not
cared much about the Crusade before, but now that the Pope had
cursed him, he made up his mind that come what might he would
reign in Jerusalem.
He set sail once more, but while he went slowly with his heavy
war ships towards Acre, a swift ship passed his fleet. It reached the
Holy Land long before he did, and two monks who had sailed in it,
and who had been sent by the Pope, raised the Christians against
him. When he landed, no welcome waited him, though he had come
to fight for the kingdom of Jerusalem against the Saracens. Although
the knights would not serve under him, yet nothing could daunt him.
He had learned the language of the Saracens, so when the
Christians would not own him he planned a treaty with their foes.
The sultan promised to give up Bethlehem, Nazareth, and the whole
of the city of Jerusalem except the part where the mosque of the
prophet had stood for ten years. But though this pleased the sultan
and Frederick, it did not please any one else. The Saracens were
angry that the Holy City had been given to the Crusaders. The Pope
and the Christians were angry that the worship of the prophet
should have any place within Jerusalem. The Pope was still more
enraged to think that the man that he had cursed would be king in
Jerusalem.
For years the Pope had been urging his people to go on
pilgrimage to Jerusalem. Many had hastened to the Holy Land, and
thought gladly now that they could do as they had vowed, but the
Pope sent messages from Rome that no one who cared for his
wishes was even to pray at the Holy Sepulchre.
Frederick entered Jerusalem. He passed through empty streets,
for priests and men and women fled from him.
He marched to the Church of the Holy Sepulchre followed by a
small band of his warriors. He entered the empty church. He saw
that the images of the apostles were veiled, and that no priest stood
by the altar. No sound of music or of song rose on the air. Only the
armour of the soldiers clanked on the pavement, and the step of
Frederick rang hard and sharp as he strode to the altar.
He lifted the crown that lay there and placed it on his head, but
none save the handful of knights who followed him owned him King
of Jerusalem.
Frederick did not long enjoy even this empty title of king. He
went back to Europe, and ere long Jerusalem was taken by other
victors than either sultan or emperor.
CHAPTER V
HOW LOUIS THOUGHT DEATH
A LITTLE THING
Before the first Crusade, the Turks had poured westward to

Palestine. Now before the last Crusade, another wild and fierce race
swept down from China on Europe. They were called Tartars, and
the terror of them spread to far countries. Villagers in France and
Italy pointed to curious clouds in the sky, and turned pale; they
thought them a sign that the monsters called Tartars were coming.
Men and women cowered away in terror at the sight of a forest fire;
they thought the Tartars had kindled it.
A wild and fierce race called Tartars

Such a tribe swept over the Holy Land: and Moslem and Christian
joined together to fight the terrible foe. But even though they fought
side by side, they could not turn the fierce warriors back. On and on
they came till their horses dashed up the streets of Jerusalem. The
city was empty. Every one had fled. But the victors were cruel men,
they wished to kill their foes as well as to take the city. They flung
the banner of the cross out against the sky, and rang glad peals on
the bells of the Christian churches. In the caves and amongst the
rocks round Jerusalem hundreds of people were hiding. They heard
the bells, and peered out to see what had happened. They saw no
foeman’s flag, but their own banner waving. The news spread from
rock to rock and from cave to cave. Crowds of joyful people hurried
back to their city and to their homes. But the pealing bells and the
floating banners drew them on only to death. The enemy waited till
all were either within the gates or close to them. Then they fell on
them and killed them.
At this time King Louis of France was a young man of twenty-six.
His father had died when he was ten. Since that time, his mother,
Queen Blanche, had guarded his lands and had trained him to be a
good and true man. She was a wise woman, and strong and
beautiful. She was kind too, and she charmed those whom she
ruled.
Louis was a handsome young king, fair and slight. His long hair
flowed over his shoulders. He did not care to wear gay clothes, for
he was prouder of the coarse hair shirt which he wore under his
armour than of all his royal robes. To all who met him, he was gentle
and courteous.
Once he was very ill. His nobles stood round his bed. They
thought he was dead. Suddenly he spoke in a hollow voice. He bade
the Bishop of Paris fasten the cross of the Holy War on his shoulder.
When he was well again many of his people wished him to stay
in France and rule them, for Louis thought of many things that
would help the people of his land. He made good laws, and he was
just and kind. Those who wished him to stay at home said that he
need not keep the promise he had made to go to fight in Palestine,
because he was so ill when he made it that perhaps he did not know
what he said. When this was said to Louis, the Bishop of Paris
chanced to be beside him again. The king snatched the cross from
his shoulder and gave it to the bishop. Then he said:
‘Now at least, I am in my senses, and I vow that no food shall
enter my lips till the cross is again on my shoulder.’
So they knew that they need not urge him again to stay.
It was Christmas Eve. The king sat in a dimly lighted hall. The
nobles of the court were called to him that he might fulfil an old
French custom of mantle-giving. It was an honour to be called, and
each man went up gladly to the king and felt a thrill of pleasure as
the folds of the mantle fell from his shoulders. The nobles went from
the king’s presence into the chapel for the Christmas Eve service. As
the bright light fell on the new cloaks, the knights started in
surprise. The Cross of the Holy War had been fastened to each
mantle. Each man saw it on his neighbour. Then he looked at his
own robe and saw it there. Some smiled; some shrank from the
vow; but the king’s will was law, and his nobles made ready to sail.
In this crusade there were no gay robes nor jewelled bridles. Nor
were there any ragged camp followers. Louis’s army was made up of
strong workmen and nobles.
The wild warrior tribe that had so cruelly killed the people of
Jerusalem had left the land again and once more the Holy City was
in the hands of the Sultan of Egypt. Louis hoped to surprise him and
to attack him at the mouth of the Nile, but the Egyptian heard that
he was coming and was ready to meet him. He brought a fleet of
ships down the Nile and he lined the shores with armies.
When the two fleets met, the ships spread over miles of water.
Close to the shore the fleet of Egypt lay. In a half-circle round it the
crusading vessels gleamed in the sunshine, and the banner of the
Cross waved from each topmast. Away out to sea one ship lay alone.
From it, Queen Marguerite, the wife of Louis, watched the battle.
In the morning, the knights who were to fight on shore led their
horses on planks from the great warships to the barges that lay
alongside. The horses lurched and plunged in the unsteady boats,
and the clang of their armour rang out across the water. All was
noise and clamour. Hundreds of rowers bent to the oars. The barges
bounded forward. Suddenly the sunlight was darkened. Spears and
arrows from the Egyptian army flew so thick around the Crusaders
that they could not see the sky. The rowers flagged. But the voice of
Louis rang out to cheer them, and they bent to the oars with greater
strength than ever. As the boat that bore the king touched the
ground, Louis leapt into the water though it reached to his shoulder,
and dashed through it sword in hand. Nobles and men followed him.
The army that lined the shore broke its ranks and fled. But almost
before the Crusaders could form in line, the horse soldiers of the
Moslem army swept down on them from the desert.
Louis was so calm that he knelt for a moment on the sand. ‘Thy
will be done!’ he murmured. Then he sprang up and rushed into the
fight. As the day wore on, Queen Marguerite as she watched, saw
the oriflamme of France push slowly up the beach. Ship after ship
that had guarded the river mouth sank. They were pierced by the
prows of the French vessels. Ere night the victory was won. The
crusading camp rang with shouts of joy.
Louis sprang into the water
In the morning a blaze of fire was seen in the south. Damietta,
the town that Louis hoped to take for his own, was in flames. The
foe had burned the city. No riches were left to tempt the army, so
the burning of the city both helped and hindered Louis. Queen
Marguerite landed and formed her court within the charred and
ruined walls of Damietta. The army waited for more ships and men.
But while they waited, bands of Arabs came whirling down on the
camp. They came to any part of it that seemed less guarded,
entered the tents, killed those they found there, and carried off the
heads of all they killed. These wild men took the heads of the
Crusaders to the sultan, who gave a golden coin for each one. Their
horses were so swift and light that they could always escape from
the heavy chargers of the knights. While the troops led by Louis
were waiting here, the sultan was busy. The town of Mansourah
stands at the place where the great river Nile breaks into many
channels and forms the delta at its mouth. There the Moslem leader
made ready to fight the French king. He built walls and towers, and
made the town strong against the armies of the Cross.
At last the Crusaders marched, but when they reached
Mansourah they found a great stream of water between them and
the city. They could not fight the foe until they had crossed the
channel. Then Louis bade his men build a causeway across the
stream. But even as they built, the enemy on the other side dug
away the sandy bank, and the stream flowed on as broad as before.
A shout was heard ‘A ford, a ford.’ It was not a good ford that
had been found, still it was possible to cross by it, and the eager
armies hastened to it. Robert, the king’s brother, begged to be
allowed to cross first with his men. He said he would wait on the
other bank and guard the ford till the rest of the army had crossed
over. A band of Moslems tried to keep him from landing. He drove
them back. They fled across the sand.
Then Robert forgot his promise to stay by the ford. The masters
of the knights of Jerusalem who rode with him begged him to think.
They knew that it was a great mistake to break away from the other
warriors. But Robert was too eager to listen. He said bitter things to
them and seemed to think that they wished to keep all the power in
their own hands. They were very angry at this, and the master of
the Templars, to show that he was neither a coward nor wilful,
shouted out:
‘Raise then the standard.’
But William Longsword of England still tried to keep Robert from
his folly.
‘What cowards these English are!’ said Robert.
But Longsword was no coward. Robert had his way. He swept on
with his followers, and chased the Moslems into their fortress of
Mansourah. But it was only one part of the Moslem army that he
defeated. Bibars, a Saracen leader, saw what had happened. He
gathered his forces, and ere Robert knew what was going on, his
foes were at Mansourah, shutting it in on every side, and he and his
men were prisoners in the town they had won. They fought all day
long. Very few of them lived to see the next morning’s sun. William
Longsword, whom Robert had called a coward, fought so bravely
that even his foes noted where he fell, and after the fight was over
gave back his body to his friends.
But long ere nightfall, Louis had crossed the ford with the other
part of the crusading army. Instead of comrades waiting to guard
their landing, they found only the track of fighting, and foes on
every side. They broke into bands. Instead of one great attack a
hundred battles were fought. The orders Louis gave could not be
heard, for his voice was drowned in the noise and clamour of armour
and of hoofs. No one knew what to do next. It seemed that all must
be lost.
Then Louis dashed forward with a small bodyguard. His haste
was so great that he left his guard behind him, and found himself
alone in the midst of six Moslem warriors. They knew he was the
king by his armour. It seemed as if he must yield. But Louis was a
great fighter, and he did not know what fear was. He held the six at
bay until his guards joined him; then with them he led his army on
in one wild charge, and won the day. But though they were victors
they had suffered so greatly that it would have been wise if they had
gone back to Damietta. This they would not do. They camped by the
battle-field, and there very many of them grew ill and died. There
was little food, and the air was evil-smelling and deadly. Louis went
in and out amongst his men. As a nurse to them he was as tender
and patient as he had been bold and fearless in war. At length he
too fell ill.
He knew that something must be done to make peace with the
sultan, for no help could come to Jerusalem from a host of Christian
soldiers who were dying on the sands of Egypt. So he sent a
message to say he would leave Egypt if the Moslems would give
Jerusalem back to the Christians. The sultan said:
‘Yes, if the king himself will be my prisoner until the last Crusader
has left Egypt.’
Louis wished to agree to this, but his nobles would not hear of it.
Since there could not be peace between the armies, there was no
escape for the Crusaders but by flight. Even that seemed hopeless.
Still it was all that could be done. Only a few of the boats which had
followed them up the Nile were left. On these they placed the sick
men and all the women and children. Then by night they set them
afloat down the stream towards Damietta. The nobles begged Louis
to go on board one of these vessels.
‘Nay, I march with the last man of mine who lives,’ said Louis. As
the army left the camp, it was attacked. Louis turned and fought
wildly for his men.
‘Wait for the king! Wait for the king!’ rang from the banks. The
vessels were stayed, but Louis signed to them to go on. At length
Louis and his men left the camp. The king was on horseback, but
without helmet or cuirass. But all their efforts were in vain. Both
ships and soldiers fell into the hands of the enemy. The king was
weak and ill, but still free. His knights saw that he could go no
further. They sought to hide him in a house in an Egyptian town,
where a humble woman from France tended him gladly. But in spite
of the knights who guarded the door, the Moslems burst into the
house and loaded King Louis with chains. They carried him to
Mansourah in a vessel gaily decked in honour of the great prisoner
they had taken. As he sailed southwards up the stream, he saw his
men driven along the banks in chains.
Louis in prison was as great a man as Louis in battle. He wore a
coarse robe, because he would not deign to wear the gay clothing
the sultan sent to him, nor would he feast with the Moslems, though
they wished him to join them.
Each day he saw some of his followers led out from prison. They
were asked if they would cease to be Christians and accept the faith
of the prophet. They refused. No sooner had they done so than they
fell dead before the eyes of their captive king. It was a terrible thing
for him to sit thus day after day and watch the men who had fought
by his side, and whom he loved, slain in this barbarous way.
When the sultan thought he had tried the king so long and so
greatly that he would be glad to agree to any terms, he offered him
freedom if he would give to him Damietta and the cities of Palestine.
Louis had won Damietta in battle, but he had no right to the cities of
the Holy Land.
‘The cities do not belong to me but to God,’ he said.
Then the sultan threatened to torture Louis to make him yield.
‘I am the sultan’s prisoner,’ said the king; ‘he can do with me as
he will.’
He was so calm and firm that a Moslem who stood by said: ‘You
treat us, sire, as if you had us in prison instead of our holding you.’
But though the sultan spoke of torturing King Louis, he did not
do it except by making him watch the men of his army as they died
before him. When he found that the king would not yield he gave in
himself, and agreed to accept Damietta in return for the king, and a
large sum of money for those of the army who still lived.
But the knights would not let Louis wait to see the men set free.
A vessel lay waiting at the mouth of the Nile. As soon as he and his
queen were on board, it sped out to sea, and ere long King Louis
was once more in France.
He was a great ruler as well as a great fighter, and he thought of
the needs and duties of those whose king he was, as none in that
land had ever done before. While he made France strong and its
people happy, Bibars, who had so cleverly trapped Robert at
Mansourah, became sultan, and laid waste the Holy Land. The news
of this reached the northern lands from which the crusading armies
had gone forth in former days, and once more the great longing to
save Jerusalem took hold of Louis. His nobles sat in council. He
came to them bearing a crown of thorns in his hands. Again he
fastened the cross of war on his shoulder. He had heard that a great
king in Africa was willing to become a Christian, and as he thought
of this he dreamed bright dreams. He thought that he might bring
this desert king and his dark followers to join his faith and his army,
and that with them to aid him, he might even yet conquer the
Moslem armies and win Jerusalem and Palestine.
His fleet sailed for the African coast. The army landed and
marched into the desert. The hot sand blew about them and choked
them. They found no friendly welcome, but only messages of blood
and war from the king whom Louis had hoped would join him in
battle against the Moslems. Illness and death swept through the
army. One of the first to die was a son of King Louis. Soon the king
himself lay dying in his tent in the hot desert camp.
‘Jerusalem, Jerusalem,’ he cried, ‘we will go to Jerusalem!’ His
couch was very comfortless, but it was not so humble as Louis
wished it to be. He bade them spread ashes on the ground and lay
him there. When they had done this, they saw his lips move. They
bent to listen, and heard these words:
‘Father, into Thy hands I commend my spirit.’
Then he fell asleep. The sleep grew deeper and deeper, and soon
the men who watched him there knew that he would never wake on
earth again.
In the dim light of the tent, on a bed of ashes, lay all that was
left of good King Louis. His beautiful face still kept the grandeur men
had loved to see all his life long. He lay there in the sad, plague-
stricken camp, and around him there seemed to linger the light of
heaven.
Louis was the last of the heroes of the Crusades, but for years
after his death the Christian forces held cities in the Holy Land. At
last they were driven from all their strongholds, and the Moslem rule
was unbroken.
To-day there is no kingdom of Jerusalem. There are ruins of
churches and of castles, and the broken walls show how great was
once the power of the armies of the Cross.
But though the dream of the Crusaders never came true, and
though all their efforts left little mark on the life of the East, yet the
lands from which the knights went out have been changed, and all
their history has been different, because of those wars to which their
armies went.
Over the door of an old house in a close in Edinburgh a scallop-
shell, like the shells that were brought by pilgrims from the Holy
Land, was cut in stone. In that house those who had made the long
journey to the East, and had come back weary or ill, were welcomed
and cared for. The shell above the door stood for hundreds of years
to tell of the olden days. It is so in the history of Europe. Those who
know it best can see the mark of the Crusades cut into the life of the
nations whose knights led the armies of the Holy War, as clearly as
the scallop-shell was cut into the old wall in Edinburgh.
Edinburgh: Printed by T. and A. Constable
A NEW SERIES FOR CHILDREN
Large Type, Pure Rag Paper
THE CHILDREN’S HEROES
Edited by JOHN LANG
‘A collection admirably adapted to the
entertainment as well as instruction of
young people.’—The Spectator.
In dainty volumes, bound in Cloth Gilt, with
Picture Design
and Silk Marker.
Also in Ornamental Boards.
Each Volume has 8 Coloured Pictures by well-
known Artists.
The aim of this series is to tell, in simple and
vivacious style, the story of those whose lives
have been distinguished by great deeds. The
child will in this way learn what has been done
in the world by leaders of men. The volumes
are also to be had in neat cloth gilt boxes, each
containing three volumes—Three Great Sailors,
Three Great Soldiers, Three Great Missionaries,
Three Great Explorers, Three Great Patriots.
LIST OF VOLUMES
1. THE STORY OF DAVID LIVINGSTONE.
By Vautier Golding; pictures by L. D. Luard.
2. THE STORY OF CAPTAIN COOK. By

John Lang; pictures by W. B. Robinson.
3. THE STORY OF NELSON. By Edmond

Francis Sellar; pictures by Monro S. Orr.
4. THE STORY OF CHALMERS OF NEW
GUINEA. By Janet Harvey Kelman; pictures by W.
B. Robinson.
5. THE STORY OF SIR WALTER

RALEIGH. By M. D. Kelly; B.A.; pictures by T. H.
Robinson.
6. THE STORY OF SIR FRANCIS DRAKE.

By L. M. Elton; pictures by T. H. Robinson.
7. THE STORY OF GENERAL GORDON.

By Jeanie Lang; pictures by W. B. Robinson.
8. THE STORY OF ABRAHAM LINCOLN.

By Mary A. Hamilton; pictures by S. T. Dadd.
9. THE STORY OF LORD CLIVE. By John

Lang; pictures by Stewart Orr.
10. THE STORY OF CHRISTOPHER

COLUMBUS. By G. M. Imlach; pictures by
Stewart Orr.
11. THE STORY OF STANLEY. By Vautier

Golding; pictures by L. D. Luard.
12. THE STORY OF BISHOP PATTESON.

By Elma Paget; pictures by S. T. Dadd.
13. THE STORY OF ROBERT THE BRUCE.

By Jeanie Lang; pictures by F. M. B. Blaikie.
14. THE STORY OF LORD ROBERTS. By

Edmund Francis Sellar; pictures by Sidney Paget,
and others.
15. THE STORY OF JOAN OF ARC. By

Andrew Lang; pictures by J. Jellicoe.
London: T. C. & E. C. JACK, 16 Henrietta Street,

W.C.
and Edinburgh
‘TOLD TO THE CHILDREN’
SERIES
Edited by LOUEY CHISHOLM, Author of ‘In
Fairyland.’
1. STORIES OF ROBIN HOOD. Told by H.
E. Marshall; pictures by A. S. Forrest.
2. STORIES OF KING ARTHUR’S

KNIGHTS. Told by Mary Macgregor; pictures by
Katharine Cameron.
3. STORIES FROM CHAUCER. Told by

Janet Harvey Kelman; pictures by W. Heath
Robinson.
4. STORIES FROM THE FAERIE QUEEN.

Told by Jeanie Lang; pictures by Rose Le Quesne.
5. UNCLE TOM’S CABIN. Abridged by H.

E. Marshall; pictures by A. S. Forrest.
6. THE PILGRIM’S PROGRESS. Abridged

by Mary Macgregor; pictures by Byam Shaw.
7. ROBINSON CRUSOE. Abridged by John

Lang; pictures by W. B. Robinson.
8. OLD TESTAMENT STORIES. Selected

by Edwin Chisholm; pictures by R. T. Rose.
9. THE HEROES. Abridged by Mary

Macgregor; pictures by Rose Le Quesne.
10. THE WATER BABIES. Abridged by Amy

Steedman; pictures by Katharine Cameron.
11. STORIES FROM THE LIFE OF

CHRIST. Selected by Janet Harvey Kelman;
pictures by F. D. Bedford.
12. STORIES FROM SHAKESPEARE. Told
by Jeanie Lang; pictures by N. Price, and others.
13. NURSERY RHYMES. Selected by Louey

Chisholm, with Forty Illustrations in colour by S.
R. Praegar and Jack Orr.
14. LITTLE PLAYS. By Lena Dalkeith,

adapted from Hans Andersen’s ‘Fairy Tales,’
‘Robin Hood,’ ‘Sir Garth of Orkney,’ and other
familiar sources; illustrated with eight coloured
photographs of little actors in costume.
15. GULLIVER’S TRAVELS. Told by John

Lang; pictures by F. M. B. Blaikie.
16. THE ROSE AND THE RING. Abridged

by Amy Steedman; pictures by W. M. Thackeray.
17. TANGLEWOOD TALES. Abridged by C.

E. Smith; pictures by Olive Allen.
18. FAIRY TALES FROM HANS

ANDERSEN. Told by Mary Macgregor; pictures
by Olive Allen.
19. FAIRY TALES FROM GRIMM. Told by

Amy Steedman; pictures by Harry Rowntree.
20. ÆSOP’S FABLES. Told by Lena Dalkeith;

47 pictures by S. R. Praeger.
21. STORIES FROM DON QUIXOTE. Told

by John Lang; pictures by F. M. B. Blaikie.
22. STORIES FROM THE ILIAD. Told by

Jeanie Lang; pictures by W. Heath Robinson.
23. STORIES OF WILLIAM TELL. Told by

H. E. Marshall; pictures by F. L. Gloag.
24. NURSERY TALES. Told by Amy
Steedman; pictures by Paul Woodroffe.
25. STORIES FROM THE ODYSSEY. Told

by Jeanie Lang; pictures by W. Heath Robinson.
26. STORIES FROM THE ARABIAN

NIGHTS. Told by Amy Steedman; pictures by F. M.
B. Blaikie.
27. STORIES OF GUY OF WARWICK.

Told by H. E. Marshall; pictures by L. D. Luard.
The following sets of three volumes in cloth

case, gilt design—Fairy Tales(Grimm,
Andersen, and Nursery Tales); Stories from
English Literature (Chaucer, Spenser,
Shakespeare).
London: T. C. & E. C. JACK, 16 Henrietta Street,
W.C.
and Edinburgh
Transcriber’s Notes:
Hyphenation and spelling have been left as originally
typeset.
Illustrations have been moved up or down from their
original position, to avoid interrupting paragraphs.
The page reference on the Frontispiece pointed to page
76; the actual text occurs on page 75. This has been
corrected.
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Before the first Crusade, the Turks had poured westward to

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2. THE STORY OF CAPTAIN COOK. By

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9. THE STORY OF LORD CLIVE. By John

10. THE STORY OF CHRISTOPHER

11. THE STORY OF STANLEY. By Vautier

12. THE STORY OF BISHOP PATTESON.

13. THE STORY OF ROBERT THE BRUCE.

14. THE STORY OF LORD ROBERTS. By

15. THE STORY OF JOAN OF ARC. By

London: T. C. & E. C. JACK, 16 Henrietta Street,

2. STORIES OF KING ARTHUR’S

3. STORIES FROM CHAUCER. Told by

4. STORIES FROM THE FAERIE QUEEN.

5. UNCLE TOM’S CABIN. Abridged by H.

6. THE PILGRIM’S PROGRESS. Abridged

7. ROBINSON CRUSOE. Abridged by John

8. OLD TESTAMENT STORIES. Selected

9. THE HEROES. Abridged by Mary

10. THE WATER BABIES. Abridged by Amy

11. STORIES FROM THE LIFE OF