Neurodegenerative Diseases: Neurobiology, Pathogenesis and Therapeutics

Cover......Page 1
Half-Title......Page 3
Title......Page 5
Copyright......Page 6
Contents......Page 7
Preface......Page 23
Contributors......Page 11
Part I Basic aspects of neurodegeneration......Page 25
Mitochondria......Page 27
Reactions of the superoxide radical......Page 28
Singlet oxygen......Page 29
Transition metal ions......Page 30
GSH......Page 31
Flavonoids and other plant antioxidants......Page 32
Superoxide dismutases (SOD)......Page 33
Glutathione peroxidases (GPX)......Page 34
Chemical analysis......Page 35
REFERENCES......Page 36
Why is identification of reactive species and biomolecular targets so difficult?......Page 42
Interminable terminology......Page 43
How can superoxide be toxic?......Page 44
Physical/chemical properties of nitric oxide......Page 45
Peroxynitrite – the predominant NO-derived oxidant (NODO)......Page 46
Other oxidative modifications by peroxynitrite......Page 47
Protein nitration in neurodegenerative diseases......Page 48
Sacrificial vs. catalytic scavengers......Page 49
Scavengers based on pharmacophores in proteins......Page 50
Why do we need so much SOD activity?......Page 51
In the presence of NO, SODs can use H2O2 to run in reverse......Page 52
ENDNOTES......Page 53
REFERENCES......Page 54
Mitochondrial energy production and sites of action for metabolic inhibitors......Page 57
Mitochondrial free radical production......Page 59
Mitochondria and cell death: necrosis......Page 60
Mitochondrial and cell death: apoptosis......Page 62
Mitochondrial inhibition and neurodegeneration......Page 63
REFERENCES......Page 64
NMDA receptors......Page 68
The neurotoxin glutamate......Page 69
Excitotoxicity and Parkinson's disease......Page 70
Huntington's disease......Page 72
Amyotrophic lateral sclerosis......Page 73
Conclusions......Page 74
REFERENCES......Page 75
Functional properties......Page 81
Topology......Page 82
Excitatory neurotransmission and glutamate transporters......Page 83
Amyotrophic lateral sclerosis (ALS)......Page 84
Huntington's disease......Page 85
REFERENCES......Page 86
Increased calcium in motor neurons in ALS......Page 89
Cellular calcium homeostasis and calcium binding proteins......Page 90
AMPA/kainate receptors and selective vulnerability......Page 92
Mechanism of protection of motor neurons by calcium binding proteins: axon terminals......Page 93
Mechanism of protection of motor neurons by calcium binding proteins: cell bodies......Page 94
In vivo studies......Page 95
Neuroprotective role of CaBPs in other systems......Page 96
REFERENCES......Page 98
Apoptosis......Page 104
Mitochondrial, endogenous pathway of apoptosis......Page 105
Evidence for apoptosis and caspase activation in human diseases......Page 107
Trauma......Page 108
Parkinson's disease......Page 109
Limitations and cautions......Page 112
REFERENCES......Page 113
Developmental motoneuron cell death......Page 118
Neurotrophic factors for motoneurons......Page 119
Identification of cellular signaling pathways responsible for neurotrophic factor mediated survival of motoneurons......Page 120
The role of neuronal activity and glutamate for motoneuron survival......Page 121
An active role of NGF signaling in motoneuron cell death?......Page 122
Downstream signals which mediate the neuronal survival response to neurotrophins and CNTF: the role of members of the IAP family......Page 124
Animal models for human motoneuron disease......Page 125
REFERENCES......Page 127
Introduction......Page 132
Selective degradation of abnormal proteins......Page 134
Protein inclusions and aggresome formation......Page 136
Proteasomal hydrolysis of polyQ-containing proteins......Page 139
Protein damage can induce apoptosis......Page 140
Key unresolved issues......Page 141
Abnormal protein inclusions in Parkinson's disease......Page 143
Apoptosis and inclusions in other neurodegenerative diseases......Page 144
Aging, Hsps, and susceptibility to neurodegenerative diseases......Page 145
REFERENCES......Page 147
Removal of oxidative lesions from DNA......Page 155
Base excision repair......Page 156
Cockayne’s syndrome......Page 157
Repair of mitochondrial DNA damage and neurodegenerative disease......Page 159
Acknowledgements......Page 161
REFERENCES......Page 162
Sodium channel blockers......Page 165
Potassium channel openers......Page 166
Calcum channel antagonists......Page 167
REFERENCES......Page 168
Poly(ADP-ribose) polymerase-1......Page 170
PARP-1 mediated neurotoxicity is executed by apoptosis inducing factor......Page 171
Excitotoxicity and experimental stroke......Page 172
Inflammatory neurodegenerative diseases......Page 173
PARP inhibitors......Page 174
REFERENCES......Page 176
Protein interactions in brain copper and zinc metabolism......Page 181
Alzheimer's disease......Page 182
Beta amyloid protein......Page 183
Superoxide dismutase 1......Page 184
REFERENCES......Page 185
14 The role of inflammation in Alzheimers disease neuropathology and clinical dementia. From epidemiology to treatment......Page 190
Implications for the potential beneficial role of NSAIDs in cases with MCI......Page 191
COX: a target for NSAIDs in AD......Page 192
Novel evidence for the beneficial role of NSAIDs in AD neuropathology......Page 193
Paradoxical role of inflammatory mediators in the brain. Implications for AD dementia......Page 194
Cell cycle, COX-2 and AD neuropathology......Page 195
Research in progress and outstanding research questions: is there a “better” NSAID for AD?......Page 196
REFERENCES......Page 197
Clinical features, pathology and genetics......Page 200
Models of ABeta amyloidosis......Page 203
Alzeimer's disease, a neuronal disease......Page 204
Potential therapeutics for Alzheimer's disease......Page 206
Clinical features, pathology and genetics......Page 207
SOD1 mutant mice......Page 208
Potential therapies for ALS......Page 209
Clinical features, pathology and genetics......Page 210
α-syn transgenic mice......Page 211
Clinical features, pathology and genetics......Page 212
Experimental therapeutics......Page 213
Conclusions......Page 214
REFERENCES......Page 215
1-Methy-4-phenyl-1,2,3,6-tetrahydropyridine......Page 220
MPTP mode of action......Page 222
Late events......Page 223
6-Hydroxydopamine and related compounds......Page 224
Paraquat......Page 227
Rotenone......Page 228
Malonate and 3-nitropropionic acid......Page 229
Other ETC mitochondrial toxins......Page 231
Neurotoxic amphetamines......Page 232
Glutamate and analogues......Page 234
REFERENCES......Page 236
First, to what extent do the entities represent single pathogenic processes?......Page 246
Fourth, what are the toxic species of these pathogenic molecules?......Page 247
Experimental therapies based on the amyloid cascade hypothesis......Page 248
REFERENCES......Page 249
Parkinson's disease (PD)......Page 251
Bradykinesia: EMG, movement studies, sensorimotor integration studies, movement-related potentials, transcranial magnetic stimulation......Page 252
Bradykinesia-: cortical function (reaction times, movement-related potentials, magnetic stimulation)......Page 256
Tremor: neuroimaging and TMS studies......Page 257
Rigidity: spinal and long loop reflexes, spinal inhibitory mechanisms......Page 258
Neurophysiological findings in experimental dyskinesias and during surgery......Page 259
Brainstem reflexes......Page 260
Spinal reflexes and spinal inhibitory circuits......Page 261
Sensory function and sensorimotor integration......Page 262
Cortical function (LLR, somatosensory evoked potentials, movement-related potentials, magnetic stimulation)......Page 263
EMG recordings......Page 264
Sensorimotor integration......Page 265
Cortical function (LLR, SEPs, premotor potentials and TMS)......Page 266
Myoclonus......Page 267
REFERENCES......Page 269
Part II Neuroimaging in neurodegeneration......Page 275
Structural MRI acquisition and postprocessing techniques......Page 277
Automated measurement of volume differences using deformation analysis......Page 278
Diffusion tensor imaging (DTI): quantitative analysis of DWI......Page 279
Structural MRI in neurodegenerative diseases......Page 280
Alzheimer’s disease......Page 281
Dementia with Lewy bodies (DLB)......Page 282
Fronto-temporal dementia (FTD)......Page 283
Atypical forms of parkinsonism and their differentiation from PD......Page 284
Motor system disorders......Page 287
Ataxias......Page 289
Prion diseases......Page 291
Variant CJD (vCJD)......Page 292
Iatrogenic and familial CJD......Page 294
Does a structurally abnormal area of cerebral tissue activate normally?......Page 295
Basic principles......Page 296
Image pre-processing and analysis......Page 297
Inter-subject variability......Page 299
Alzheimer’s disease......Page 300
Other dementias......Page 301
Parkinson’s Disease......Page 302
Other extra-pyramidal syndromes......Page 303
Motor system disorders......Page 304
REFERENCES......Page 305
Dopamine transporter imaging......Page 314
Dopa decarboxylase activity......Page 315
Postsynaptic dopaminergic function......Page 316
Functional brain imaging......Page 317
Interventional modulation of brain glucose metabolism in PD......Page 319
Conclusions......Page 320
REFERENCES......Page 321
Introduction......Page 325
Evaluation of neurochemistry......Page 327
NAA......Page 331
Lactate......Page 332
Glutamate and Aspartate......Page 333
Quantification of proton spectroscopy......Page 334
31P spectroscopy......Page 336
13C NMR spectroscopy......Page 338
Use of MRS in studies of therapeutics in humans......Page 339
Neuroprotection in animal models......Page 341
Combined MRS and MRI of excitotoxicity......Page 344
REFERENCES......Page 345
Part III Therapeutic approaches in neurodegeneration......Page 351
Delivery vectors for gene transfer into the nervous system......Page 353
Adenovirus derived vectors......Page 354
Herpes simplex virus (HSV)-derived vectors......Page 356
Adeno-associated virus (AAV) derived vectors......Page 357
Retrovirus derived vectors......Page 359
Examples of therapeutic strategies......Page 360
Parkinson’s disease......Page 361
Mucopolysaccharidosis type VII (MPS-VII)......Page 362
REFERENCES......Page 363
Neural stem cells of the mammalian forebrain......Page 371
Huntington’s disease as a prototypic target for neural stem cell-based therapy......Page 372
Embryonic stem cells as a replenishable source of dopaminergic neurons......Page 374
Stem and progenitor cell-mediated treatment of Alzheimer’s and the cholinergic depletions......Page 375
Compensatory neurogenesis as a predictor of inducible neuronal replacement......Page 376
Intraventricular viral expression vectors can target subependymal progenitor cells......Page 377
BDNF overexpression induces heterotopic neuronal recruitment to the adult neostriatum......Page 378
Synergistic strategies for inducing striatal neurogenesis from endogenous progenitor cells......Page 379
Induction of resident progenitors as a means of restoring dopaminergic input to the striatum......Page 380
Progenitor stimulation as a restorative strategy for the hippocampal atrophies......Page 381
REFERENCES......Page 382
Introduction......Page 387
It is necessary to obtain structural reconstitution of terminal synaptic function and regulated dopamine release by new dopamine neurons......Page 388
Technical developments of a new technology for regeneration of neural function and pathways in patients......Page 392
Subpopulations of midbrain dopaminergic neurons perform different functions and reach different targets: its potential relevance to repair of PD brains......Page 393
Can we produce better therapies with fewer sideeffects by accomplishing a more specific cellular and synaptic dopamine replacement?......Page 394
How can stem cell biology research help Parkinson patients?......Page 396
REFERENCES......Page 398
Part IV Normal aging......Page 405
Epidemiologic aspects of aging......Page 407
Memory in humans......Page 408
Memory in rodents......Page 409
Imaging studies of age-related changes in cognition......Page 410
Changes in motor function with age......Page 412
Neuronal loss and neurotransmitter changes......Page 413
White matter changes......Page 414
REFERENCES......Page 415
Hippocampal pathology in AD......Page 420
Lesion types and cortical distribution......Page 421
Summary: AD and cortical circuitry......Page 422
The aging synapse: non-human primate studies......Page 423
Age-related changes in rat hippocampus......Page 425
Interactions between neural and endocrine senescence......Page 426
Conclusions and future directions......Page 427
REFERENCES......Page 428
Part V Alzheimer's disease......Page 431
Normal aging and evolution to MCI......Page 433
Clinical description......Page 434
History and examination......Page 435
Biomarkers......Page 436
AAN practice parameters......Page 437
REFERENCES......Page 438
First description/historical overview......Page 440
Clinical features......Page 441
History, bedside mental status examination, neurological examination......Page 442
Laboratory evaluation......Page 443
Neuroimaging......Page 444
Pathogenesis/mechanisms of disease......Page 445
Amyloid precursor protein isoforms in platelets......Page 447
Progressive visual disturbance......Page 448
Symptomatic treatment: acetylcholinesterase inhibitors......Page 449
Selegiline and alpha-tocopherol (vitamin E)......Page 450
Secretases and immunotherapy......Page 451
REFERENCES......Page 452
The ABeta theory of Alzheimer’s disease and the problem of selective vulnerability......Page 457
Classical histological changes ABeta amyloid plaques......Page 458
Tau-related neurofibrillary tangles (NFT)......Page 459
The clinical biochemistry of ABeta in AD......Page 460
REFERENCES......Page 461
Early-onset Alzheimer's disease......Page 465
The APOE locus on chromosome 19......Page 468
Chromosome 12......Page 469
Chromosome 10......Page 471
Conclusions......Page 472
REFERENCES......Page 473
Beta-amyloid plaques are major histophathological hallmarks of Alzheimer’s disease......Page 476
Beta-amyloid-related toxicity causes the formation of neurofibrillary tangles......Page 477
Aggregation of soluble ABeta into insoluble Beta-amyloid fibrils......Page 478
Immunization against Beta-amyloid......Page 479
REFERENCES......Page 480
Introduction......Page 483
Galantamine......Page 484
Quality of life and economic benefit of cholinesterase inhibitors......Page 485
Treatment of vascular and mixed dementia with agents approved for AD......Page 486
Vitamin E......Page 487
Anti-inflammatory agents......Page 488
Lowering homocysteine......Page 489
Lowering lipids......Page 490
Conclusions: the challenge of managing a neurodegenerative disease......Page 491
REFERENCES......Page 492
Part VI Other dementias......Page 495
Introduction......Page 497
Pathogenesis and heritability......Page 498
Clinical characterization......Page 499
Laboratory evaluations and brain imaging......Page 501
Management......Page 502
REFERENCES......Page 503
First description and history of FTLD......Page 505
Corticobasal ganglionic degeneration (CBD; see also Chapter 45)......Page 507
The role of tau protein in FTLD pathogenesis......Page 508
FTLD clinical syndromes......Page 509
Clinical variants......Page 510
Epidemiology......Page 511
Imaging......Page 512
Genetics......Page 513
REFERENCES......Page 514
Familial frontotemporal dementia......Page 518
Frontotemporal dementia with parkinsonism linked to chromosome 17......Page 520
Biology of the tau protein......Page 521
Clinical features of FTDP-17......Page 522
Neuropathology of FTDP-17......Page 524
Effects of FTDP-17 mutations......Page 525
Conclusions......Page 529
REFERENCES......Page 530
Epidemiology......Page 536
Sporadic CJD......Page 537
Diagnostic procedures......Page 538
EEG (Fig. 36.2)......Page 539
Genetic CJD (gCJD)......Page 540
Epidemiology......Page 541
Kuru......Page 542
Symptomatic treatment......Page 543
REFERENCES......Page 544
Prion biology: some basic facts......Page 547
Some major open questions in prion biology......Page 548
Peripheral entry sites of prions......Page 549
Oral prion susceptibility correlates with number but not structure of Peyer's patches......Page 550
Transepithelial enteric passage of prions: a role for Mcells?......Page 551
Lymphocytes and prion pathogenesis......Page 552
Prion hideouts in lymphoid organs......Page 553
Neuroinvasion proper: the role of sympathetic nerves......Page 556
Macrophages and toll-like receptors......Page 558
Adaptive immunity and pre-exposure prophylaxis against prions......Page 559
Prion immunization and its reduction to practice......Page 560
The prion doppelganger......Page 561
Consequences of Doppel deficiency: a detour to reproductive pathology......Page 562
REFERENCES......Page 565
Part VII Parkinson's and related movement disorders......Page 573
General symptomatology of patients with parkinsonism......Page 575
Clinical signs constituting the syndrome of parkinsonism......Page 576
Other signs to evaluate......Page 577
The epidemiology of the differential forms of parkinsonism......Page 578
Anatomy, physiology and biochemistry as they apply to the clinical signs of parkinsonism......Page 579
Clinical approach to the investigation of parkinsonism......Page 581
REFERENCES......Page 582
Biochemical patterns of vulnerability (neurochemistry)......Page 585
Concepts regarding etiology......Page 586
Other clinical features......Page 588
Subtypes of Parkinson's disease......Page 589
Time course of the disease......Page 590
Neuroimaging......Page 591
REFERENCES......Page 592
Pathology of PD......Page 599
Lewy bodies (LBs) and Lewy neurites (LNs)......Page 601
Composition of LBs......Page 602
What is the earliest pathology in PD?......Page 604
Other pathology in PD......Page 605
Clinicopathologic correlations in PD......Page 606
REFERENCES......Page 607
Introduction and historical background......Page 610
Monogenic forms of Parkinson's disease......Page 611
Cellular and animal models......Page 612
PARK5: Parkinsonism associated with a mutation in the gene for ubiquitin hydrolase L1......Page 613
PARK2: autosomal recessive juvenile parkinsonism (AR-JP) caused by mutations in the gene for parkin......Page 614
Non-monogenic forms of familial PD......Page 615
REFERENCES......Page 617
Oxidative stress......Page 622
Dopamine......Page 623
Neuromelanin......Page 624
Mitochondrial dysfunction......Page 625
Exotoxins......Page 626
Apoptosis......Page 627
Lewy bodies and protein aggregation......Page 628
REFERENCES......Page 629
Mitochondrial dysfunction......Page 636
Inflammation......Page 637
Levodopa......Page 638
Dopaminergic agonists......Page 639
Monoamine oxidase B (MAO-B) inhibitors......Page 640
Intervention in the malfunctioning circuitry......Page 641
Regeneration......Page 642
REFERENCES......Page 643
Historical review......Page 647
Morphological pattern of vulnerability......Page 648
Biochemical findings......Page 650
Molecular biology......Page 652
Pathogenesis/mechanism of disease......Page 653
Parkinsonism......Page 655
Dysautonomia......Page 656
Other clinical features......Page 657
Clinical variants and their frequency......Page 659
Time course of the disease......Page 661
Prognosis......Page 662
Cardiovascular function......Page 663
Bladder function......Page 664
Magnetic resonance imaging (MRI)......Page 665
Functional imaging......Page 668
Other investigations......Page 670
Autonomic failure......Page 671
Motor disorder......Page 672
Acknowledgements......Page 673
REFERENCES......Page 674
Presentation......Page 687
Radiologic evaluation......Page 688
Tau protein......Page 690
Clinical correlates......Page 691
Pathoanatomy......Page 693
Brainstem centers controlling sleep and arousal......Page 694
Incidence......Page 695
A clue from FTD......Page 696
Cholinergics and anticholinergics......Page 697
Patient resources......Page 698
REFERENCES......Page 699
Historical review......Page 706
Anatomical pathology......Page 707
Molecular pathology......Page 709
Clinical features......Page 710
CBD-like syndromes due to other pathologies......Page 714
Imaging......Page 715
Electrophysiology......Page 716
REFERENCES......Page 717
Part VIII Cerebellar degenerations......Page 721
Diagnostic approach to the patient with ataxia......Page 723
Ataxia disorders with highly characteristic phenotypes......Page 724
Autosomal recessive inheritance......Page 725
Genetic causes of sporadic adult-onset ataxia......Page 727
Myoclonus......Page 728
Management of ataxia patients......Page 729
REFERENCES......Page 730
CAG repeat/polyglutamine ataxias......Page 733
The spinocerebellar ataxias......Page 735
SCA2......Page 736
SCA4......Page 737
SCA10......Page 738
Episodic ataxias......Page 739
REFERENCES......Page 740
Epidemiology......Page 743
Pathological features......Page 744
FRDA mutations......Page 745
Frataxin mitochondrial localization......Page 746
Frataxin and iron homeostasis......Page 747
Frataxin as an iron-storage protein......Page 748
Mouse models for FRDA......Page 749
Ataxia due to isolated vitamin E deficiency (AVED)......Page 750
Abetalipoproteinemia (ABL)......Page 751
Refsum disease (RD)......Page 752
Ataxia + blindness + deafness (SCABD)......Page 753
Spinocerebellar ataxia + neuropathy 1 (SCAN1)......Page 754
Spastic ataxia of Charlevoix-Saguenay (ARSACS)......Page 755
REFERENCES......Page 756
Neuropathogenesis......Page 762
Molecular genetics......Page 763
Cancer susceptibility......Page 765
Laboratory diagnosis......Page 766
Treatment......Page 768
REFERENCES......Page 769
Part IX Motor neuron diseases......Page 773
Examination......Page 775
Management of the patient......Page 776
Bulbar dysfunction......Page 777
Nutritional support......Page 778
Other common symptoms......Page 779
REFERENCES......Page 780
Familial ALS and the first descriptions......Page 782
Linked genetic loci in familial ALS......Page 783
Cytosolic Cu/Zn superoxide dismutase (SOD1)......Page 784
ALS2......Page 785
Sporadic ALS......Page 786
Epidemiological studies......Page 787
Genetic studies-SOD1......Page 788
Genetic studies-candidate gene association studies......Page 789
Conclusions......Page 791
REFERENCES......Page 792
Testing therapies in transgenic mice......Page 796
Current and future therapies for ALS......Page 797
Excitotoxicity......Page 798
Trial data......Page 799
Prescription guidelines for riluzole......Page 800
Anti-oxidant drugs......Page 801
Bioenergetic modifiers......Page 802
Gingko biloba......Page 803
Xaliproden......Page 804
Celecoxib......Page 805
Diseasemodifying agents for other motor neuron disorders......Page 806
Sodium butyrate......Page 807
Neurotrophic factors......Page 808
Hereditary spastic paraplegia (HSP)......Page 809
Candidate approach via clarification of molecular biology......Page 810
REFERENCES......Page 811
Clinical signs and symptoms of uncomplicated HSP......Page 818
Neurologic examination......Page 820
Treatment......Page 821
HSP genes......Page 822
Conclusions......Page 823
REFERENCES......Page 824
Clinical background......Page 827
Genetics and molecular biology......Page 829
Molecular basis of polyglutamine neurotoxicity......Page 831
Molecular basis of motor neuron degeneration in SBMA......Page 832
Towards therapy......Page 836
REFERENCES......Page 837
Clinical picture......Page 841
Diagnostic findings......Page 843
Genetics/molecular biology......Page 845
Non-proximal SMA......Page 847
Future prospects......Page 848
REFERENCES......Page 849
Introduction......Page 851
Parkinsonism--dementia complex of Guam......Page 852
Neurofibrillary tangles......Page 853
Eosinophilic rod-like inclusions (Hirano bodies)......Page 854
Other microscopic features......Page 855
Neuropathologic studies of Chamorros of Guam with intact neurologic function......Page 856
Other foci of ALS/parkinsonism--dementia complex......Page 857
Nature vs. nurture......Page 858
Migration studies of the Chamorros of Guam......Page 859
Infectious organisms......Page 860
Cycad......Page 861
Toxic metals......Page 862
REFERENCES......Page 863
Part X Other neurodegenerative diseases......Page 869
Introduction......Page 871
HD as a Mendelian disorder......Page 872
Differential diagnosis......Page 874
The classic phenotype......Page 875
Assessment of neurological and functional decline......Page 876
Non-motor signs and symptoms......Page 877
The Huntington's disease gene, the Huntington's disease protein ("Huntingtin") and the Huntington's disease mutation......Page 878
REFERENCES......Page 880
Molecular biology......Page 885
Pathogenesis......Page 886
Proteolytic processing of atrophin-1......Page 887
Clinical picture......Page 888
Investigations......Page 889
Treatment......Page 890
REFERENCES......Page 891
Chorea-acanthocytosis (ChAc)......Page 895
McLeod syndrome......Page 897
Hypolipoproteinemias......Page 898
Other rare neuroacanthocytosis syndromes......Page 899
REFERENCES......Page 900
Neuroferritinopathy......Page 904
Ceruloplasmin......Page 905
Aceruloplasminemia: genetics......Page 906
Aceruloplasminemia: clinical features......Page 907
Aceruloplasminemia: pathogenesis......Page 909
Hallervorden--Spatz syndrome......Page 910
REFERENCES......Page 911
Introduction......Page 914
Neurological manifestations of WD......Page 915
Epilepsy in WD......Page 917
Abnormalities of clinical neurophysiology in WD......Page 918
Neuropathological changes in WD......Page 919
Making the diagnosis of WD......Page 920
Genetics and pathophysiology of WD......Page 922
The toxicity of copper......Page 923
Initial treatment......Page 924
REFERENCES......Page 925
Introduction......Page 933
CPEO and KSS......Page 934
Myopathy encephalopathy lactic acidosis and stroke-like episodes......Page 936
Neurogenic muscle weakness ataxia and retinitis pigmentosa (NARP)......Page 937
Myo-neuro-gastrointestinal encephalopathy (MNGIE)......Page 938
Parkinson's disease......Page 939
Huntington's disease......Page 940
Friedreich's ataxia......Page 941
REFERENCES......Page 942
Index......Page 951