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TitleAutism - Current Theories and Evidence - A. Zimmerman (Humana, 2008) WW
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00
	Autism
		CURRENT CLINICAL NEUROLOGY
		Autism: Current Theories and Evidence
		Preface
			Moving Beyond Hypotheses: A Call for Theories and Evidence
			Quotations from Leo Kanner
			Definition
			References
		Contents
		Contributors
		List of Color Plates
01
	Part 1: Molecular and Clinical Genetics
01a
	ENGRAILED2 and Cerebellar Development in the Pathogenesis of Autism Spectrum Disorders
		Introduction
			History of Autism
			ASD Neuropathology and Pathogenesis
		Cerebellar Development, Function, and ASD
			Cerebellar Development
			Postnatal Cerebellar Development
			Cerebellar Patterning Genes
			Patterning Gene Expression
			Combinatorial Gene Expression Confers Cell-Specific Identity
			Biochemical and Molecular Signals in Cerebellar Development
			Cerebellar Abnormalities in ASD
			Effects of Cerebellar Abnormalities in ASD
		Extracerebellar Functional Deficits in ASD
		En2 Transgenic Mice Phenocopy ASD Cerebellar Neuropathology
			Molecular Abnormalities in En2 Mutant Mice
			Overexpression of En2 also Results in ASD-Like Cerebellar Pathology
			Functional Deficits in En2 Mutant Mice
		ASD Genetic and Environmental Etiology
			Thalidomide and VPA
			Twin Studies in ASD
			Rett Syndrome and Epigenetic Regulation
			Genes of Interest in ASD
			Endophenotypes and ASD Genes
		ENGRAILED-2 is an Autism-Associated Gene
		En2 Function During Cerebellar Development
		Preliminary Data
			En2 and IGF-1
		Conclusion
		References
02
	Teratogenic Alleles in Autism and Other Neurodevelopmental Disorders
		Introduction
		Approaches to Documenting Action of a Teratogenic Allele
		Examples of Teratogenic Alleles
			Documentation of a Teratogenic Allele by Maternal Transmission Disequilibrium Test
				MTR*2756G and MTRR*66G as Teratogenic Alleles for Spina Bifida
				GSTP1*313A and GSTP1*341C as Teratogenic Alleles for Autism
			Documentation of a Teratogenic Allele by Maternal Transmission Disequilibrium Test Equivalent
				Maternal Phenylketonuria
				Rh Incompatibility
			Documentation of a Teratogenic Allele by the Log-Linear Method
				The MTHFD1*653Q Allele and Spina Bifida
				The CYP1A1*6235C Allele and Low Birth Weight
				NAT1 Alleles and Spina Bifida Risk
				The CCL-2*(-2518)A Promoter Allele and Spina Bifida Risk
			Documentation of a Teratogenic Allele by Regression Methods
				Maternal Alleles Influence Newborn Lipoprotein Concentrations
				Maternal GSTP1 Alleles and the Asthma Phenotype in Children
			Documentation of a Teratogenic Allele by Case-Control Methods Plus Case Transmission Disequilibrium Test
				Maternal MTHFR 677T Allele as a Risk Factor for Cleft Lip With or Without Cleft Palate (CL/P)
				Maternal MTHFR 677T Allele as a Risk Factor for Congenital Heart Disease
				Maternal MTHFR 677T Allele as a Risk Factor for Down Syndrome
				HLA-DR4 as a Risk Factor for Autism
			Suggestion of a Teratogenic Allele by Case-Control Methods Without Case Transmission Disequilibrium Test
				Complement C4B*0 and HLA-DR4 as Possible Teratogenic Alleles for Autism
				The GSTP1*1b Allele as a Possible Teratogenic Allele for Recurrent Early Pregnancy Loss
				The MTHFR*1298C Allele as a Possible Teratogenic Allele for Spina Bifida
				Methylenetetrahydrofolate Reductase (MTHFR)*677T and Methionine Synthase Reductase (MTRR)*66G as Possible Teratogenic Alleles for Down Syndrome
				Glutathione S-Transferase Deletion Allele (GSTT1*0) as a Possible Teratogenic Allele for Oral-Facial Clefting
				MTHFR*1298C as a Possible Teratogenic Allele for Spina Bifida
				The Glutathione S-Transferase Gene Deletion Allele, GSTM1*0, as a Possible Risk Factor for Recurrent Pregnancy Loss
				The Dihydrofolate Reductase 19-Basepair Deletion Allele, A Possible Teratogenic Allele for Spina Bifida
				The CYP1A1*2A Allele as a Possible Teratogenic Allele for Recurrent Pregnancy Loss
				The DHFR 19-bp Deletion Allele as a Possible Teratogenic Allele for Preterm Delivery
				The Methylenetetrahydrofolate Reductase (MTHFR)*1298C Allele as a Possible Teratogenic Allele for Down Syndrome
			Potential Examples of Teratogenic Alleles
			A Word About Mechanisms by Which Teratogenic Alleles Act
		Teratogenic Alleles and Autism
		References
03
	Cholesterol Deficit in Autism: Insights from Smith-Lemli-Opitz Syndrome
		Introduction
		Cholesterol Pathways and SLOS
		Cholesterol-Related Mechanisms in ASD
		Treatment Approaches
		Conclusion
		Recommendations
		References
04
	Autism in Genetic Intellectual Disability: Insights into Idiopathic Autism
		Introduction
			General Issues
			Background on Genetic Disorders Associated with Idiopathic Autism
				Fragile X Syndrome
				Down Syndrome
				Rett Syndrome
		Clinical and Behavioral Features of Genetic Disorders Associated With Autism: Implications for Idiopathic Autism or Autism Spectrum Disorders
			Autism in Fragile X syndrome: Deficit in Complex Social Interaction and Adaptive Socialization, with Severe Social Withdrawal but no Regression
			Autism in Down Syndrome: Complex and Simple Stereotypic Behaviors and High Prevalence of Regression
			Autism in Rett Syndrome: Preserved Communication and Motor Function With Regression
		Insights into the Neurobiology of Idiopathic Autism
			Neurobiology of Fragile X Syndrome and Autism Spectrum Disorder: Anomalies of the Cerebellar Vermis and Limbic Dysfunction
			Neurobiology of Down Syndrome and Autism Spectrum Disorders: Cerebellar Enlargement and Stereotypies
			MeCP2Deficiency and the Neurobiology of Autism Spectrum Disorders
		Genetic and Molecular Pathways Common to Autistic Disorders
			Molecular Basis of Fragile X Syndrome and Autism Spectrum Disorders: Cytoplasmic FMR1-Interacting Protein 1 and Other Downstream Fmrp Targets
			Molecular Basis of Down Syndrome and Autism Spectrum Disorders: Genes Involved in Early Brain Development
			Mecp2 Levels are Dysregulated in Idiopathic Autism Spectrum Disorders
		Concluding Remarks
		References
05
	Part 2: Neurotransmitters and Cell Signaling
05a
	Serotonin Dysfunction in Autism
		Introduction
		The Role of Serotonin in Cortical Development and Plasticity
		Neurotrophins, BDNF, and Serotonin
		Serotonin and Immune Activation
		Animal Models, Serotonin, and Autism
		Summary
		References
06
	Excitotoxicity in Autism: The Role of Glutamate in Pathogenesis and Treatment
		Introduction
		Excitotoxicity and Autism
			Evidence for Excitotoxicity in Autism
				Laboratory Findings
				Magnetic Resonance Spectroscopy
				Postmortem Data
				Immune Studies
				Relationship to Other Disorders
				Genetic Studies
		Implications for Treatment
		Summary
		References
07
	Prenatal b2-Adrenergic Receptor Signaling and Autism: Dysmaturation and Retained Fetal Function
		Introduction
		The b2-Adrenergic Receptor
			Functions
			Regulation of b2-Adrenergic Receptor Signaling
			Polymorphisms of the b2-Adrenergic Receptor
		Animal Studies
		What is the Relationship to Autism?
		Relating the Model to Autism Research
			Neuroglial Activation
			Increased Cerebral White Matter
			Insulin-like Growth Factor-1
			Glial Fibrillary Acidic Protein, Bcl-2, and GAD67
			Epilepsy
			Sulfation, Methylation, and Oxidative Stress
			Porphyrins
			Plasma and Whole Blood Serotonin
			Oxytocin
			The Gastrointestinal Tract
			The Immune System
			The Autonomic Nervous System
			Differences in Signal Transduction
		Different Mechanisms, Similar Result
		Prenatal b2-Adrenergic Receptor Overstimulation and Sensitization to Other Factors
		Effects on Other Neurotransmitter Systems
		The Role of Maternal Factors
		Prenatal b2-Adrenergic Receptor Understimulation
		Conclusion
		References
08
	Part 3: Endocrinology, Growth, and Metabolism
08a
	A Role for Fetal Testosterone in Human Sex Differences: Implications for Understanding Autism
		The Extreme Male Brain Theory of Autism
		Hormones and Sexual Differentiation
		Atypical Fetal Hormone Environments
			Congenital Adrenal Hyperplasia
			Complete Androgen Insensitivity Syndrome
			Idiopathic Hypogonadotropic Hypogonadism
		Hormonal Effects: Indirect Studies in Typical Populations
			Digit Ratio (2D:4D)
			Dermatoglyphics
			Lateralization
			Pubertal Onset
			Co-Twin Sex
		Hormonal Effects: Measurements of Fetal Testosterone
			Maternal Sampling During Pregnancy
			Samples from the Umbilical Cord
			Amniotic Fluid
			Cambridge Fetal Testosterone Project
				Fetal Testosterone and Eye Contact at 12 Months
				Fetal Testosterone and Vocabulary at 18 and 24 Months
				Fetal Testosterone and Empathy at Age 4
				Fetal Testosterone, Restricted Interests, and Social Relationships at Age 4
				Fetal Testosterone, Systemizing, Empathizing at Ages 6-8
				Behaviors Associated with ASC
				Fetal Testosterone and Autistic Traits
			Limitations of Amniocentesis Methods
		Conclusions
		References
09
	Interaction between Genetic Vulnerability and Neurosteroids in Purkinje cells as a Possible Neurobiological Mechanism in Autism Spectrum Disorders
		Introduction
		Organizing Role of Sex Hormones in Neuronal Growth and Survival
		Sex Steroids Regulate Neuronal Death and Survival
		The Loss of Cerebellar Purkinje Cells in ASD
		Estrogens Influence Cerebellar PC Growth, Maturation, and Survival
		The Male Heterozygous Reeler Mouse: A Possible Heuristic Model of Cerebellar Pathology in ASD
		Future Research Avenues
		References
10
	Insulin-Like Growth Factors: Neurobiological Regulators of Brain Growth in Autism?
		What are Neurotrophic Factors?
		Insulin-Like Growth Factors
		Insulin-Like Growth Factors and Head Growth
		Insulin-Like Growth Factors and Specific Brain Cells
		Autism and Head Growth
		Age
		Neuropathology
		Studies on Autism and Neural Growth Factors
			The Finnish Study
				CSF IGF-1 and IGF-2 in Autism
				Serotonin and IGF
		Autism and Rett Syndrome
		Serum IGF-1
		Conclusion
		References
11
	Oxidative Stress and the Metabolic Pathology of Autism
		Introduction
			Oxidative Stress
			Glutathione and Redox Homeostasis
		Hypothesis and Evidence Linking Oxidative Stress and Autism
			Single Gene Disorders
			Prenatal and Peri-Natal Environmental Exposures
			Gender Disparity in Autism
			Clinical Pathology of Autism and Oxidative Stress
			Summary
		Gene-Environment Interactions Affecting Glutathione and Redox Imbalance
			Pro-Oxidant Environmental Exposures
			Oxidative Stress During Neurodevelopment
			Genes, Environment, and the Autism Metabolic Phenotype
		Systemic Implications of Oxidative Stress and Autism Metabolic Pathology
			Autism Metabolic Phenotype
			Gut-Brain-Immune Connection Applied to Autism
		Future Prospects
		References
12
	The Immune System in Autism: Is There a Connection?
		Introduction
		Autoantibodies in Autism Spectrum Disorder
		Maternal Antibodies to Fetal Brain
		Immune Dysfunction in Children with ASD
		Making the Final Connections
		References
12a
	Part 4: Immunology, Maternal-Fetal Interaction, and Neuroinflammation
13
	Maternal Immune Activation, Cytokines and Autism
		Introduction: Genes Versus Environment in Autism
		Environmental Factors in Autism
		Maternal Immune Activation: Poly(Inosine:Cytosine)
		Maternal Immune Activation: Lipopolysaccharide
		Maternal Immune Activation: Periodontal Bacteria
		Other Protocols of Immune Activation
		Maternal Immune Activation Elevates Cytokines in the Fetal Environment
		Pro/Anti-Inflammatory Balance Mediates Maternal Immune Activation Effects on the Fetus
		Cytokines and Autism
		Mechanisms of Cytokine Action and Potential Therapies
		Perspectives
		References
14
	Maternal Antibodies and the Placental-Fetal IgG Transfer Theory
		Introduction
		Hypothesis
		Supporting Evidence
			Circumstantial Evidence
				HLA Studies
				Maternal Influences
				Hygiene Hypothesis
				Clinical Examples of Maternal Antibodies Altering Fetal Human Development
			Direct Evidence
				Presence of Anti-Fetal Brain Antibodies in MCAD
				Association Between Presence of Maternal Antibodies Against Fetal Brain Tissue and Developmental Regression in Offspring with Autism
				Pregnant Dam (Mouse) Model
		Discussion
		Summary
		References
15
	Can Neuroinflammation Influence the Development of Autism Spectrum Disorders?
		Introduction
		Immune Responses and the Central Nervous System
		What is Neuroinflammation
		The Influence of Neuroimmune Responses in Brain Development
		Roles of Neuroglia During Brain Development
		Neurodevelopmental Roles of Cytokines and Chemokines
		Major Histocompatibility Complex and Complement Cascades in Brain Development and Synaptogenesis
		Neuroglia and Neuroimmune Responses During Adulthood
		Neuroglia and Synaptic Plasticity
		How May Neuroimmune Responses Influence the Pathogenesis of Autism Spectrum Disorders
		Maternal Factors in the Modulation of Neuroimmune Responses
		Chronic Neuroimmune Reactions in Autism Spectrum Disorder
		Genetic Susceptibility and Immune Responses in Neurological Disease
		Conclusion
		References
16
	Part 5: Neuroanatomy and Neural networks
16a
	The Significance of Minicolumnar Size Variability in Autism: A Perspective from Comparative Anatomy
		Introduction
		Minicolumnar Pathology in Autism
		Minicolumns
			Methodological Considerations
			Trends for Between-Area Minicolumnar Variability
			Minicolumnar Variability Differences Between Species
			Functional Implications of Increased Minicolumnar Variability
		Conclusions
		References
17
	Imaging Evidence for Pathological Brain Development in Autism Spectrum Disorders
		Clinical Presentation
		Structural Imaging Relationships
		Magnetic Resonance Spectroscopy
		Testing models of apoptotic/synaptic pruning deficits in ASD
		Testing Models of Accelerated Brain Growth in ASD
		Summary
		References
18
	Information Processing, Neural Connectivity, and Neuronal Organization
		Introduction
		Complex Information Processing-Disconnectivity-Neuronal Organization Model of Autism
		Principles of Neurological Disorders
		General Principles of Developmental Neurobiologic Disorders
		Forming a Neurologically Based Model for Autism: Origins of Our Model
		Empiric Evidence for Our Model: Disordered Complex Information Processing
		Concept Formation: A Common Theme and Predictor of Underconnectivity with Frontal Cortex
		Visual Processing: Another Example of Generalized Integrative Processing Deficits
		A Dual-Task Experiment: Support for the Complex Information Processing Model
		Postural Control: Evidence of Abnormal Connectivity and Broad Involvement of the Brain
		The Neural Basis of Autism: The Origin of Functional Underconnectivity
		Disturbances in the Development of Neural Circuitry: A Second Disruption in Development
		Social Impairments in Autism
		Autism as a Disorder of Cortical Development
		Summary
		References
19
	Part 6: Environmental Mechanisms and Models
19a
	Evidence for Environmental Susceptibility in Autism: What We Need to Know About Gene * Environment Interactions
		Introduction
		Developmental Neurotoxicants and Autism
			Cholinergic Agents
			Relevance to Autism
		Chemicals that Interfere with GABA Neurotransmission
			Relevance to Autism
		Chemicals that Interfere with Calcium Signalling
		Ca2+ and Neuronal Connectivity: How Chemicals can Make a Good Plan go Bad
		References
20
	An Expanding Spectrum of Autism Models: From Fixed Developmental Defects to Reversible Functional Impairments
		Introduction
		Reflection on Autism Models
		From Behavioral to Multi-Leveled Nosology
			A Modular ‘‘Bottom-Up’’ Approach: Genes–Brain–Behavior
			The Critical Nature of Models and Diversity in Scientific Investigation
				Limits of a ‘‘Gene–Brain–Behavior’’ Model
			A Systems Pathophysiology ‘‘Middle-Out’’ Approach: Dysregulated Biology
				Analogies with multiple sclerosis
		Links Between Expanded Biological Hierarchy and Expanded Temporal Axis
			Delayed Onset of Autism
			Neurodegeneration
			Improvement and Recovery
		From a Static Defect in Early Circuit Development to a Chronic Ongoing Disturbance of Circuit Remodeling and Function
			A Model of Static Encephalopathy (Fig. 20.2)
			Genetic Static Encephalopathy (Fig. 20.2, Model 1a)
			Static Encephalopathy Caused by Gene-Environment Interactions (Fig. 20.2, Model 1b)
			A Model of Autism as a Chronic Condition (Fig. 20.2, Model 2)
				Epigenetic Contributors and Potential Plasticity (Fig. 20.2, Model 2a)
				Ongoing Environmental Contributors to Chronic Encephalopathy (Fig. 20.2, Model 2b)
				Autism as Trait vs. Autism as Trait Modulated by State vs. Autism as State
				Autism as Trait Modulated by State
				Autism as Predominantly State Rather than Trait
				Mistaking State for Trait
		Chronic Mechanisms in Functional Impairment in Autism
			Disturbances of Astroglial Function
			Neuronal and Neural Circuit Changes from Astroglial Metabolic and Structural Changes Deriving from Chronic Inflammation
			Release of Inhibitory and Excitatory Neuromodulators
			Retraction of Glial Processes
			Dismantling and Collapse of Synapses and Dendrites
			Glial Calcium Oscillations
			Sustaining Inflammation
			Summary of Glial Impacts: The Foregoing as Examples of New Classes of Mechanisms to Pursue
			Implications for Heterogeneity, Reversibility, Autism Symptoms, and Development–Chronicity Interactions
			The Challenge of Generic Mechanisms in a Specifically Described Disorder
		Summary and Conclusion
		References
back-matter
	Index
                        
Document Text Contents
Page 2

Autism

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9 Interaction between Genetic Vulnerability and Neurosteroids 227

Page 478

Recurrent pregnancy loss (RPL) and
glutathione S-transferase (GST),
59–60

Reduced folate carrier 1 gene (RFC1), 44
Reelin (RELN) extracellular glycoprotein, 23
Retinoic acid response element (RARE),

regulator of HOX gene
expression, 21

Rett syndrome (RTT), 22–23, 82, 271
and Autism, 239–240

Serum IGF-1in, 241
MECP2 gene, 91

Rh Disease and fetal development, 313
Rh incompatibility disorders in fetus, 50
Rhombencephalon, 6
Risperidone, 5-HT2A-receptor antagonist,

140
Ryanodine receptors (RyR) in brain and

autism, 417
RyR-dependent mechanisms, neuronal

connectivity and synaptic
plasticity, 421–422

SAM/SAH methylation ratio, 246, 257, 258,
261

Schizophrenia, 289, 290, 292, 293, 298, 338
Selective serotonin reuptake inhibitors

(SSRIs), 112
Serotonin (5-hydroxytryptophan/5-HT),

neurotransmitter, 111–112
cortical development and plasticity,

113–114
and immune activation, 115–116
neurotrophins and, 114–115
Serotonin1A (5-HT1A) receptor, 76
serotonin system, dysfunction, 76
serotonin transporter (SERT) binding

capacity, 239
Sexually dimorphic nucleus of medial

preoptic area (SDNPOA), 211
Sib pair methods, 45. See also

Teratogenic alleles
Sjøgren’s syndrome, 276
SLC25A12 gene, 138
Smith-Lemli-Opitz syndrome (SLOS)

biochemical analyses for, 77
cholesterol pathways, 70–74
clinical diagnosis of, 70
defect in cholesterol synthesis, 75
7-DHC level and phenotypic

abnormalities, 70
facial features of, 71
phenotypic features of, 73

social and languagecommunication
impairments, 72

sterol abnormality associated with, 74–75
treatment approaches, 76–77
webbing and, 72

Sodium valproate, 140. See also Autism
Sonic hedgehog (Shh), extracellular growth

factors, 8
Spinal nucleus of bulbocavernosus (SNB),

214
Stromal-derived factor-1(SDF-1), 334
Superoxide dismutase (SOD1)

antioxidant enzymes, 160, 248
Synaptogenesis, 334–335
Syndactyly (webbing), 72
Systemic lupus erythematosus (SLE), 275,

314
Systemizing quotient (SQ), 186, 187, 198, 199

Tachykinin 1 (TAC1) gene, 139
Telencephalon of forebrain, 6
Teratogenic alleles, 42, 45

action mechanisms, 45–48, 62–63
and autism, 63
case-control methods plus case TDT,

maternal MTHFR 677T allele as
risk factor

CHD for, 54
for cleft lip with/ without cleft palate

(CL/P), 53–54
Down syndrome for, 54–55

case-control methods without case TDT
complement C4B*0 and HLA-DR4 as

alleles for autism, 56
CYP1A1*2A allele for recurrent

pregnancy loss, 60–61
DHFR 19-bp deletion allele as allele

for preterm delivery, 61
dihydrofolate reductase 19-basepair

deletion allele for spina bifida, 60
GSTM1*0 as risk factor for recurrent

pregnancy loss, 59–60
GSTP1*1b allele as allele for recurrent

early pregnancy loss, 56–57
GSTT1*0 as allele for Oral–Facial

Clefting, 58–59
MTHFR*1298C allele for Down

syndrome, 61–62
MTHFR*1298C allele for spina

bifida, 57, 59
MTHFR*677T and MTRR*66G as

alleles for Down syndrome, 58
case genetic effect, 47

Index 473

Page 479

Teratogenic alleles, 42, 45 (cont.)
log-linear method

CCL-2*(-2518)A promoter allele and
spina bifida risk, 52

CYP1A1*6235C allele and low birth
weight, 51

MTHFD1*653Q allele and spina
bifida, 51

NAT1 alleles and spina bifida risk,
51–52

maternal imprinting in, 46
maternal transmission disequilibrium test

GSTP1*313A and GSTP1*341C for
autism, 49

maternal phenylketonuria (PKU),
49–50

MTR*2756G and MTRR*66G for
spina bifida, 48–49

Rh incompatibility disorders, 50–51
regression methods

maternal alleles and newborn
lipoprotein concentrations, 52

maternal GSTP1 alleles and asthma
phenotype in children, 52–53

reports of, 43–44
Terbutaline

B2AR agonist, 153–155
effect on ASD, 313

Tetrahydrofolate (THF)-dependent
methionine transmethylation and
glutathione synthesis, 247

Thalidomide and ASD susceptibility, 21
Timothy syndrome, 281
Tourette syndrome (TS), 275
Toxaphene usage and GABA

neurotransmission, 415
Tuberous sclerosis (TS) and autism, 251

Uterine natural killer (uNK) cells role in
pregnancy, 299

Valproic acid (VPA)
administration and ASD susceptibility,

21
anticonvulsant, 137
model for austism, 119–120

Velocardiofacial syndrome (VCFS), 82
Vesicular monoamine transporter

(VMAT2), 113
VZ-derived deep cerebellar nuclear

precursors, 11–12

Weschler Adult Intelligence Scale, 191

Zebrin II (aldolase-C), 14

474 Index

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