Autistic Disorder
Autistic Disorder, sometimes referred to as early
infantile autism or childhood autism is:
 between 1 i...
Demographics (old thoughts)
Old teaching Prevalence: 1-1.5 /10,000
(those who are more inclusive quote higher
figures)
Mal...
California
UK
Autism is a Spectrum
Different symptoms in different patients
Autism is affected by many other variables
 Age of onset
 ...
Autism: Clinical Picture
Autism: Cardinal symptoms
Speech and language delays
Social relatedness difficulties
‘Other’ beha...
Autism
Pervasive Developmental Disorder
 Autism
 Rett Disorder
 Asperger Disorder
 Childhood Disintegrative Disorder
...
Autistic
Disorder
Rett
Disorder
Childhood
Disintegrative
Disorder
Asperger
Disorder
PDD NOS
Pervasive Developmental
Disord...
DIAGNOSTIC CRITERIA FOR AUTISTIC
DISORDER
A. A total of six (or more) items from (1), (2), and (3), with at least
two from...
Austim: Diagnosis
2. Qualitative impairments in communication as manifested by at
least one of the following:
a. delay in,...
Autism: Diagnosis
3. Restricted, repetitive and stereotyped patterns of behavior,
interests and activities, as manifested ...
Asperger Disorder
Qualitative impairments in social interaction, as manifested by at least 2
of the following:
 (1) impai...
Asperger Disorder
Clinically significant impairment in social, occupational,
or other important areas of functioning
No cl...
Rett Disorder
All of the following
 (1) apparently normal prenatal and perinatal development
 (2) apparently normal psyc...
Childhood Disintegrative Disorder
Apparent normal development for at least the first 2 years after
birth
Clinically signif...
What might lead to Autism?
Familial: Genetic (inherited) and micro-
environment (family, emotional)
Environmental: toxins,...
Savant Skills in
Autism Spectrum Disorders
•Developmental disorders -- including Autism --
display expertise, ability, or ...
Savant Skills in Autism Spectrum Disorders:
Differential Diagnoses
• Differential diagnoses of ‘savant skills’
•Autism Spe...
Savant Skills in Autism Spectrum Disorders
• Study of Savant Skills in Autism (Rutter)
•N = 137
•IQ from Severe to Superio...
Savant Skills in
Autism Spectrum Disorders
•Case Report of an ASD Student with savant skills: Math and
music
•Enhanced cog...
Savant Skills in
Autism Spectrum Disorders
•Management of the ASD Student with savant skills
•Foundation is a solid neuro-...
Management of PDD inattention, impulsivity
Medical treatment
 Attention deficit
Analeptics: Ritalin, Concerta, Metadate, ...
Medical Treatment of PDD Compulsive behaviors
Compulsive behaviors,rituals, and behavioral rigidity
 SSRIs
Prozac, Luvox,...
Medical Management of PDD
Aggression
Agitation and aggression
 SSRIs
 Atypical and typical neuroleptics
(risperidone, ha...
Medical Management of PDD
Sleep
Insomnia
 Music, waterbed, structured time
 Melatonin
 Clonidine
 Tricyclics (amitript...
Vitamin Approaches to Autism
If a metabolic disorder is caused by a enzyme,
which binds to a co-enzyme – inefficient
enyzy...
Familial/Genetic Data
Autism Spectrum Disorders trend in certain
families
 Identical twin – high number of identical twin...
Genetic Contributions to Autism
Greenberg 2001
 Affected sib pair study
High in twins
30 were twins both mono (12) and Di...
Chromosomal Evidence
Chromosomes compose genes; genes code
for various building blocks and processes in
the body
Evidence ...
Genetic Mapping of Autism
Point mutations
 15q11-q13 deletion
 Maternal
 Small % of population
Proximal area of C 15
Mu...
Metabolic Approaches to Autism
PKU
 Low phenylalanine diet prevents (not
reverses) autistic symptoms
Adenylosuccinate lya...
Biochemical Theories of Autism
Serotonin
 Studies of increased 5HT
Schain, Abramson,
Piven
 Sib pair (both with Autism) ...
Biochemical Theories of Autism
Opioid Excess
 Opioids involved in endocrine regulation
 Increased opioids in urine of Au...
Biochemical Theories of Autism
 Gluten/casein metabolized to opioid compounds
 Naltrexone affects autism
 Fatty acids
...
Biochemical Theories of Autism
Amino acids
 Problem with Methylation
Histamine
DNA
Serotonin
 Gut involvement
Biochemical Theories of Autism
CCK and IGF
 Oxytocin
Pitocin induced mothers
Sulfation problems
Copeptides, which naltrex...
Metabolic Approaches to Autism
Autism - Celiac Disease Connection
 Connection of wheat-gluten/milk-casein and
Mental Diso...
Biochemical Theories of Autism
 Stress and immunity
Cytokines
 Immune messengers
 Inflam response
 CNS
 Affects hypot...
Biochemical Theories of Autism
Autoimmune Theories
 Ab in Autistic brain
myelin basic protein
Neuron-axon filament protei...
Biochemical Theories of Autism
Vaccination theory (Wakefield)
 Autism provoked by allergic reaction to vaccine
 Increase...
Immunological Observations
 B-Cells
 Frequency of C4B null allele
(MHC-III)
 TNF- (MKC-III)
 (HLA-DR+T Cells)
Immunological Observations
Natural Killer (NK)
  40% in Autism
T-Cells
  CD4+ in subset Autism
 Shift away from Th1 (...
How might the immune system be
involved with Autism?
 MHC (histocompatabilty locus) may affect
neural development
 May i...
Neurological Conditions: Autistic
behaviors
Neurological development disorders – that have
Autism as a component
 Rett Sy...
Neurological Conditions: Autistic
behaviors
Neurological development disorders – that have
Autism as a component
 Rett Sy...
Environment Evidence
Concept: there is some sinister toxin or chemical that causes
Autism
Brick Township Data
 Brick Town...
Environmental Data (Continued)
Prenatal (pregnancy exposure to chemicals)
 Alcohol
 Chemical abuse (meth)
 Prescription...
Neurophysiological Studies
EEG: 70% with abnormalities; ~20-25%
with seizures
EEG mapping: ABNL
EP: P300, N60, BAERs
Magne...
Brain imaging in Autism
First studies indicated ABNL CT scans
 Dilated ventricles
 Damasio and Mauer
MRI Studies
 Overa...
Brain imaging in Autism
Evidence for early brain overgrowth
 Overall increased volume
Limbic
Cerebral
Followed by slow or...
Brain imaging in Autism
PET/SPECT
 Asymmetry of metabolism in adults
L>R; reverse in NL
 Hypoperfusion of temporal lobes...
Brain imaging in Autism
More PET/SPECT
 smaller number of cortical metabolic correlations (asymmetries)
 delayed pattern...
fMRI
Subjects were high functioning able to
perform in fMRI machine
 Less perfusion of fusiform gyrus (compared
with norm...
Autopsy Studies
Bauman: ABNL in temporal areas, cerebellum (Purkinje
and other cells), and temporal areas
Extended finding...
Dietary Approaches to Autism
Diet designed to minimize the formation of
toxic products
Low gluten
 Removes proteins which...
Secretin
1996, published in 1998, Horvath et al.reported dramatic improvement
in a child with Autism and chronic diarrhea
...
Immunological Therapies
Transfer Factor
 Low molecular weight molecule produced
by T-Cells
 Subjects had LC response; au...
Immunological Therapies
Pentoxifylline
 Phosphodiaesterase inhibitor
 Effects
Cytokines
Inhibits TNF-alpha
Hemodynamic
...
Immunological Therapies
IVIG (iv - Ig-G)
 Retrospective study, 10 children treated for
other disorders had improvement in...
Metabolic Approaches to Autism
PKU
 Low phenylalanine diet prevents (not
reverses) autistic symptoms
Hyperuricosuric auti...
Causes of Autism
‘Autism Spectrum’ is just that a number of disorders, or
conditions that show as similar behavior syndrom...
Conclusions in Autism
Cardinal triad of Language delays, Social aberrancies, and ritualistic,
compulsive behavior
Neuropsy...
Savant Skills in Autism Spectrum
Disorders
•Delopm entsl disorders including Autism, display
expertise, ability, or brilla...
Neurological Conditions: Autistic
behaviors
Neurological development disorders – that have
Autism as a component
 Rett Sy...
Action
Continued study on the genetic, and neurological origins of
Autism
*Early identification of Autism
System of profes...
Neurological Conditions: Autistic
behaviors
Neurological development disorders – that have
Autism as a component
 Rett Sy...
Psychiatric Diagnoses are Unique
Psychiatric, Neuropsychiatry, Mental disorders are different
from medical disorders:
base...
Slide 1 - College of Education - The University of Iowa
Slide 1 - College of Education - The University of Iowa
Slide 1 - College of Education - The University of Iowa
Slide 1 - College of Education - The University of Iowa
Slide 1 - College of Education - The University of Iowa
Slide 1 - College of Education - The University of Iowa
Slide 1 - College of Education - The University of Iowa
Slide 1 - College of Education - The University of Iowa
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Slide 1 - College of Education - The University of Iowa

  1. 1. Autistic Disorder Autistic Disorder, sometimes referred to as early infantile autism or childhood autism is:  between 1 in 500 (2/1000) to 1 in 166 children (6/1,000) have an ASD.  Four times more common in boys than in girls  Children with this disorder have a moderate to severe range of communication, socialization, and behavior problems.  Many children (70%) with autism also have mental retardation (not Kanner Autism).
  2. 2. Demographics (old thoughts) Old teaching Prevalence: 1-1.5 /10,000 (those who are more inclusive quote higher figures) Male >>female Brick Township study found ASD 6-7/1000 Controversy over increase in California since 1980
  3. 3. California UK
  4. 4. Autism is a Spectrum Different symptoms in different patients Autism is affected by many other variables  Age of onset  IQ (ability to problem solve) First group described by Leo Kanner – ‘high functioning’ bright children with unusual behaviors But now it is said that 70% of Autistic individuals have IQs in the mentally disabled range  Environment Educational Family
  5. 5. Autism: Clinical Picture Autism: Cardinal symptoms Speech and language delays Social relatedness difficulties ‘Other’ behaviors  stereotypies (flapping, twirling, spinning, socking))  preservative behaviors (watch same video over and over, carry around same stuffed animal, blanket)  ritualistic behaviors (food rituals, bedtime rituals)  Difficult time with transitions (room changes, sameness)  Sensitive to environment (sounds, lights, crowds
  6. 6. Autism Pervasive Developmental Disorder  Autism  Rett Disorder  Asperger Disorder  Childhood Disintegrative Disorder  PDD NOS
  7. 7. Autistic Disorder Rett Disorder Childhood Disintegrative Disorder Asperger Disorder PDD NOS Pervasive Developmental Disorders All types of PDD are neurological disorders that are usually evident by age 3. In general, children who have a type of PDD have delayed development of: •Language and communication •Social functioning •& •Abnormal ways of relating to the world (compulsive behaviors)
  8. 8. DIAGNOSTIC CRITERIA FOR AUTISTIC DISORDER A. A total of six (or more) items from (1), (2), and (3), with at least two from (1), and one each from (2) and (3). 1. Qualitative impairment in social interaction, as manifested by at least two of the following: a. marked impairment in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body postures, and gestures, to regulate social interaction. b. failure to develop peer relationships appropriate to developmental level. c. a lack of spontaneous seeking to share enjoyment, interests or achievements with other people eg: by a lack of showing, bringing or pointing out objects of interest. d. lack of social or emotional reciprocity.
  9. 9. Austim: Diagnosis 2. Qualitative impairments in communication as manifested by at least one of the following: a. delay in, or total lack of, the development of spoken language not accompanied by an attempt to compensate through alternative modes of communication such as gesture or mime. b. in individuals with adequate speech, marked impairment in the ability to initiate or sustain a conversation with others. c. Stereotyped and repetitive use of language or idiosyncratic language d. lack of varied, spontaneous, make-believe play or social imitative play appropriate to developmental level.
  10. 10. Autism: Diagnosis 3. Restricted, repetitive and stereotyped patterns of behavior, interests and activities, as manifested by at least one of the following: a. encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus. b. apparently inflexible adherence to specific nonfunctional routines or rituals. c. stereotyped and repetitive motor mannerisms eg: hand or finger flapping or twisting, or complex whole-body movements. d. persistent preoccupation with parts of objects.
  11. 11. Asperger Disorder Qualitative impairments in social interaction, as manifested by at least 2 of the following:  (1) impairment in the use of multiple nonverbal behaviors  (2) failure to develop peer relationships appropriate to developmental level  (3) lack of spontaneous seeking to share enjoyment  (4) lack of social or emotional reciprocity Restricted repetitive and stereotyped patterns of behavior, interests, and activities, as manifested by at least one of the following:  (1) preoccupation with at least one stereotyped and restricted patterns of interest that is abnormal either in intensity or focus  (2) inflexible adherence to specific, nonfunctional, routines rituals  (3) stereotyped and repetitive motor mannerisms  (4) persistent preoccupation with parts of objects
  12. 12. Asperger Disorder Clinically significant impairment in social, occupational, or other important areas of functioning No clinically significant general delay in language (e.g. single word used by age 2 years, communicative phrases used by age 3 years). No clinically significant delay in cognitive development or in the development of age-appropriate self-help skills, adaptive behavior, and curiosity about the environment in childhood
  13. 13. Rett Disorder All of the following  (1) apparently normal prenatal and perinatal development  (2) apparently normal psychomotor development through the first 5 months after birth  (3) normal head circumference at birth Onset of the following after a period of normal development  (1) deceleration of head growth between the ages of 5 and 48 months  (2) loss of previously acquired hand skills between ages 5 and 30 months (hand washing/clapping movements)  (3) loss of social engagement early in the course (may develop later)  (4) appearance of poorly coordinated gait or trunk movements  (5) severely impaired expressive and receptive language development with severe psychomotor retardation
  14. 14. Childhood Disintegrative Disorder Apparent normal development for at least the first 2 years after birth Clinically significant loss or previously acquired skills (before 10 years) in at least 2 of the following:  (1) expressive/receptive language  (2) social skills or adaptive behavior  (3) bowel or bladder control  (4) play  (5) motor skills Abnormalities of functioning in at least 2 of the following areas:  (1) qualitative impairment in social interactions  (2) qualitative impairments in communication  (3) restricted, repetitive, and stereotyped patterns of behavior, interests, and activities, including motor stereotypes and mannerism
  15. 15. What might lead to Autism? Familial: Genetic (inherited) and micro- environment (family, emotional) Environmental: toxins, vaccines, etc. Biochemical Immunological Dietary Complex interactions produce the clinical symptoms
  16. 16. Savant Skills in Autism Spectrum Disorders •Developmental disorders -- including Autism -- display expertise, ability, or brilliance that contrast with the individual’s overall limitations •10% ASD youngsters show savant traits •Of those with savant traits, 50% display symptoms compatible with ASD •Daniel Tammet, British high-functioning autistic savant (mathematical synesthaesia, language absorption, and memory).
  17. 17. Savant Skills in Autism Spectrum Disorders: Differential Diagnoses • Differential diagnoses of ‘savant skills’ •Autism Spectrum Disorder Distance, numbers, comedy, state capitals, chess, hyperlexia •Tourette Syndrome Calendar, hyperlexia •Obsessive Compulsive Disorder Numbers, calendar •Neurological disorders – rare dementia •Common: Neuropsychiatric Disorders affect frontal-limbic system
  18. 18. Savant Skills in Autism Spectrum Disorders • Study of Savant Skills in Autism (Rutter) •N = 137 •IQ from Severe to Superior •Criteria for ‘Savant’; 1SD above gen population or 2SD above patients own 39 28% Savant skill 15 ‘Outstanding cognitive skill’ (block design) 16 Parent report 8 both cognitive and parent-reported savant skill 33% males >> 19% females No patient with VIQ < 50 demonstrated savant skill
  19. 19. Savant Skills in Autism Spectrum Disorders •Case Report of an ASD Student with savant skills: Math and music •Enhanced cognitive functions •Good memory •Superior mental calculation •Superior visual=spacial processing •Week central coherence •Only brain area with difference = thickened superior parietal cortex •Conclusion = Detail-focused processing, enhanced through over- learning and massive exposure
  20. 20. Savant Skills in Autism Spectrum Disorders •Management of the ASD Student with savant skills •Foundation is a solid neuro-psych evaluation •Medicine •Speech Therapy •Education •Psychology •Design on a solid education program •Parents •Local school and medical professionals •AEA •UIHC
  21. 21. Management of PDD inattention, impulsivity Medical treatment  Attention deficit Analeptics: Ritalin, Concerta, Metadate, (methylphenidate), Dexedrine, Adderall (dextroamphetamine)  Side effects May  SIB, self-stim, compulsiveness (although some reports indicate a  )  appetite, sleep, social, and occasionally  irritability Clonidine and Tenex (gaunfacine)  May improve attention without increasing compulsiveness Tricyclics  Often beneficial with regard to attention and aggression  Monitor side effects: dry mouth, constipation EKG Others (seizures) Bupropion (Wellbutrin) Strattera
  22. 22. Medical Treatment of PDD Compulsive behaviors Compulsive behaviors,rituals, and behavioral rigidity  SSRIs Prozac, Luvox, Zoloft, Celexa, Paxil, (fluoxetine, fluvoxamine, sertraline, citalopram, paroxetine)  Side effects: insomnia, anorexia, restlessness, impotence  Anafranil (clomipramine; tricyclic side effects)  Neuroleptics -- esp the ‘atypical’ agents (even though there may not be differences in response) Risperidone, ziprazidone (Geodon) Olanzepine (Zyprexa) More traditional: Haldol, etc. Negative study with Seroquel (quetiapine)  Alpha Agents (clonidine, Tenex)  Possibly Venlafaxine (Effexor)  Namenda
  23. 23. Medical Management of PDD Aggression Agitation and aggression  SSRIs  Atypical and typical neuroleptics (risperidone, haloperidol)  Mood stabilizers Tegretal and Depakote  Tricyclics  Tenex and clonidine  Naltrexone  Lithium
  24. 24. Medical Management of PDD Sleep Insomnia  Music, waterbed, structured time  Melatonin  Clonidine  Tricyclics (amitriptyline, imipramine most soporific)  Trazedone  ? Remeron, Lunesta, etc.
  25. 25. Vitamin Approaches to Autism If a metabolic disorder is caused by a enzyme, which binds to a co-enzyme – inefficient enyzyme function (Maple Syrup Disease) Pyridoxine  Some improvement  Folic acid may improve behavior in Fragile X (stabilizes fragile site)
  26. 26. Familial/Genetic Data Autism Spectrum Disorders trend in certain families  Identical twin – high number of identical twins exhibit autism and fraternal twins Identical twins = same genetic material (egg spits); fraternal twins = siblings  Greater chance of an autistic child’s sibling (brother, sister) showing a developmental disorder than a non autistic child’s sibling  Looking backwards (parents) more neuropsychiatric disorder (Obsessive-compulsive Disorder; Learning Disabilities). This has been called ‘The Lesser Variant’ by some)
  27. 27. Genetic Contributions to Autism Greenberg 2001  Affected sib pair study High in twins 30 were twins both mono (12) and Di (17)  Risks Twins Fetal development Other genetic or nongenetic factors Ed Cook  Susceptibility genes  HOXA1, GABRA5, FXS, VIPRA
  28. 28. Chromosomal Evidence Chromosomes compose genes; genes code for various building blocks and processes in the body Evidence for genes on certain chromosomes  Chromosome 2  Chromosome 3 (GAT1 – GABA; OXTR)  Chromosome 7 (RELN – neural development; FOXP2 – speech)  Chromosome 15 (GABA)  X chromosome (X-linked; Rett Syndrome
  29. 29. Genetic Mapping of Autism Point mutations  15q11-q13 deletion  Maternal  Small % of population Proximal area of C 15 Multiple loci (Risch, 1999)  1p, 17p Philippe  Nonparametric linkage study 2q, 7q, 6p, 19p Copy Number Variation (CNV), ~11% of PDD
  30. 30. Metabolic Approaches to Autism PKU  Low phenylalanine diet prevents (not reverses) autistic symptoms Adenylosuccinate lyase deficiency (12 reported cases) Hyperuricosuric autism  Low purine diet Lactic aciduria  Thiamine or ketogenic diet may improve
  31. 31. Biochemical Theories of Autism Serotonin  Studies of increased 5HT Schain, Abramson, Piven  Sib pair (both with Autism) 5ht > Autism without sib 5HT  Affects of SSRIs on symptoms  Increased 5HT metabolites in urine (IAG, 3-indoleacetate) Dopamine  Neuroleptics  Affect stereotypies Opioids  Affect behavior  Naltrexone
  32. 32. Biochemical Theories of Autism Opioid Excess  Opioids involved in endocrine regulation  Increased opioids in urine of Autistic children Eg. Casomorphine, morphine mod peptide…  Dipeptydal peptidase deficiency (DDP-IV) Proline Metabolizes opioids Chm 7 Gluten Genetic or acquired (auto-immunity) ?stem cell  Demorphin and Sauvagine In urine of Autistic children Gut produced Affect endocrine and CNS Demorphine affects EEG, behavior, gut Affect mu, delta receptors  Opioids affect immune system
  33. 33. Biochemical Theories of Autism  Gluten/casein metabolized to opioid compounds  Naltrexone affects autism  Fatty acids  Increased gamma interferon  Low free sulfates System affects serotonin Cysteine
  34. 34. Biochemical Theories of Autism Amino acids  Problem with Methylation Histamine DNA Serotonin  Gut involvement
  35. 35. Biochemical Theories of Autism CCK and IGF  Oxytocin Pitocin induced mothers Sulfation problems Copeptides, which naltrexone releases, in CNS  Vasopressin
  36. 36. Metabolic Approaches to Autism Autism - Celiac Disease Connection  Connection of wheat-gluten/milk-casein and Mental Disorders (Autism, ADHD, Schizophrenia)  Diet did not affect Autistic behaviors  No autistic children in 120 subjects with diagnosed Celiac Disease  8 Subjects with Autism and steatorrhea and hypocaluria did not improve on gluten free diet (Coleman)
  37. 37. Biochemical Theories of Autism  Stress and immunity Cytokines  Immune messengers  Inflam response  CNS  Affects hypothal, and locus ceruleus  Abnl in Autism
  38. 38. Biochemical Theories of Autism Autoimmune Theories  Ab in Autistic brain myelin basic protein Neuron-axon filament protein  Virus related Relationship between measles Autism Autoimmunes related  M>F  Concordance monodyzogtic  Triggered by virus  Maternal autoAB  Histocomp loci  Ab to brain areas
  39. 39. Biochemical Theories of Autism Vaccination theory (Wakefield)  Autism provoked by allergic reaction to vaccine  Increase incidence w MMR  Damage neuronal conduction Prefrontal areas 1922, polio vaccine – GBS DPT – brain damage  Symptoms Convulsions, fever due to vaccine Behavior changes
  40. 40. Immunological Observations  B-Cells  Frequency of C4B null allele (MHC-III)  TNF- (MKC-III)  (HLA-DR+T Cells)
  41. 41. Immunological Observations Natural Killer (NK)   40% in Autism T-Cells   CD4+ in subset Autism  Shift away from Th1 (to Th2)  IL-2, IFN-  IL-4 TNF (macrophages and *T-cells)   In one study CD4 CD8
  42. 42. How might the immune system be involved with Autism?  MHC (histocompatabilty locus) may affect neural development  May influence a child’s susceptibility to infections  Abnl intracellular signal transduction could underlie immune and CNS Molecular switching mechanisms MHC 1 proteins - signal transduction and gene activation
  43. 43. Neurological Conditions: Autistic behaviors Neurological development disorders – that have Autism as a component  Rett Syndrome MECP2 located on the X chromosome and can arise (1) sporadically or (2) from germline mutations  Neurofibromatosis Neurofibromatosis type 1 - mutation of neurofibromin chromosome 17q11.2 Neurofibromatosis type 2 - mutation of merlin chromosome 22q12  Tuberous Sclerosis mutations on either of two genes, TSC1 and TSC2, which encode for the proteins hamartin and tuberin respectively  Fragile X expansion (excessive repetition) of a single trinucleotide gene sequence (CGG) on the X chromosome, and results in a failure to express the FMR-1 protein
  44. 44. Neurological Conditions: Autistic behaviors Neurological development disorders – that have Autism as a component  Rett Syndrome MECP2 located on the X chromosome and can arise (1) sporadically or (2) from germline mutations  Neurofibromatosis Neurofibromatosis type 1 - mutation of neurofibromin chromosome 17q11.2 Neurofibromatosis type 2 - mutation of merlin chromosome 22q12  Tuberous Sclerosis mutations on either of two genes, TSC1 and TSC2, which encode for the proteins hamartin and tuberin respectively  Fragile X expansion (excessive repetition) of a single trinucleotide gene sequence (CGG) on the X chromosome, and results in a failure to express the FMR-1 protein
  45. 45. Environment Evidence Concept: there is some sinister toxin or chemical that causes Autism Brick Township Data  Brick Township in NJ, built on a toxic dump  Data that the rate of Autism is much higher in this area than elsewhere  Ongoing studies Mercury Controversy  Those who feel that the increase in Autism correlates with the increasing use of mercury in childhood vaccine  VERY controversial  Some interesting data correlating the two issues  However a conference dismissed the linkage, despite controversy Retroactive pesticides, chemicals, lead, and toxins
  46. 46. Environmental Data (Continued) Prenatal (pregnancy exposure to chemicals)  Alcohol  Chemical abuse (meth)  Prescription drugs Stress Mother’s stress  Stressful family environment, pregnancy or infancy Abuse and Neglect  Clinically we see children who exhibit symptoms compatible with autism, but had poor prenatal care, or early deprivation, or emotional/physical abuse
  47. 47. Neurophysiological Studies EEG: 70% with abnormalities; ~20-25% with seizures EEG mapping: ABNL EP: P300, N60, BAERs Magnetoencephalogram  82% of ASD had ABNL
  48. 48. Brain imaging in Autism First studies indicated ABNL CT scans  Dilated ventricles  Damasio and Mauer MRI Studies  Overall ABNLS  Cerebellum Courchesne  Lobules 1-5 wnl Lobules 6,7 ABNL, hypoplasia  87 % vermal hypo  13% vermal hyperplasia
  49. 49. Brain imaging in Autism Evidence for early brain overgrowth  Overall increased volume Limbic Cerebral Followed by slow or arrested growth  Sup Temp Sulcus  ‘Growth without guidance’ However  Decreased corpus collosal size  No change in limbic , or a decrease size in some frontal areas
  50. 50. Brain imaging in Autism PET/SPECT  Asymmetry of metabolism in adults L>R; reverse in NL  Hypoperfusion of temporal lobes Gilberg (children)  Less activation of L Superior Temporal Gyrus Boddeart
  51. 51. Brain imaging in Autism More PET/SPECT  smaller number of cortical metabolic correlations (asymmetries)  delayed pattern of frontal cortical metabolic maturation (hypoperfusion) Alpha-[11C]methyl-L-tryptophan (AMT) , a tracer for measuring the synthesis of serotonin, has been used with PET. A few small studies using PET after administration of AMT, primarily of children with autistic disorder, have demonstrated striking anomalies of serotonin synthesis in boys.
  52. 52. fMRI Subjects were high functioning able to perform in fMRI machine  Less perfusion of fusiform gyrus (compared with normals)  Amygdala, and frontal-temporal neocortex Phos MR  Minshew Dorsal prefrontal cortex, decreased levels of phosphocreatine
  53. 53. Autopsy Studies Bauman: ABNL in temporal areas, cerebellum (Purkinje and other cells), and temporal areas Extended findings (Bauman, Kemper): ABNL nicotinic receptors 40-50% below (granular layer, molecular layer, Purkinje cells); M1 M2 receptors OK Another study found ABNL GABA binding (WNL 5HT, Chol, Glutamine Realmutto (Minni) looked at Reelin (glycoprotein) and Bcl-2 (protein w/ programmed cell death) ABNL in ASD cerebellum Hopkins: Cerebellum and found Glut and Excitatory Amino Acid Transporter ABNL Bauman:  GABA in hippocampal area (WNL 5HT, DA, M1, M2, others)
  54. 54. Dietary Approaches to Autism Diet designed to minimize the formation of toxic products Low gluten  Removes proteins which produces toxic peptides  ? Effects 40-60% ASD with chronic diarrhea  Several have had gut changes like celiac disease  Putatively increases gut permeability  ?Fungal, but no research
  55. 55. Secretin 1996, published in 1998, Horvath et al.reported dramatic improvement in a child with Autism and chronic diarrhea Theories involve noxious peptides, may X-react with brain receptors, gut-brain connection, influences other neurotransmitters, increases blood flow, immunomodulator… Owley, Cook et al. (2001): DBPCX-over: no effect for secretin Roberts et al. (2001): No differences in RDBPC Coniglio et al. (2001): transient slight effect Dunn-Geier et al. (2000): RDBPC no group differences Chez et al. (2000): some benefits in open label, little in small group of DBPC X-over. Transient, few clinically meaningful changes Robinson (2001): Homeopathic secretin worsens sx Sandler et al. (1999): PC, DB, not effective
  56. 56. Immunological Therapies Transfer Factor  Low molecular weight molecule produced by T-Cells  Subjects had LC response; autoantibodies to MBP  Improvement in AD Subjects  Wakefield is carrying out a trial in England
  57. 57. Immunological Therapies Pentoxifylline  Phosphodiaesterase inhibitor  Effects Cytokines Inhibits TNF-alpha Hemodynamic Serotonin (and other) synthesis and release  Open label, case studies encouraging
  58. 58. Immunological Therapies IVIG (iv - Ig-G)  Retrospective study, 10 children treated for other disorders had improvement in Autism symptoms (Gupta)  Why? ? Correction of Antibody abnormality ? Immunomodulation on lymphokines Molecular mimicry of nerve cells  Another study was negative (Plioplys)
  59. 59. Metabolic Approaches to Autism PKU  Low phenylalanine diet prevents (not reverses) autistic symptoms Hyperuricosuric autism  Low purine diet Lactic aciduria  Thiamine or ketogenic diet
  60. 60. Causes of Autism ‘Autism Spectrum’ is just that a number of disorders, or conditions that show as similar behavior syndromes ‘Causes’ have to be listed as unknown, but most likely include (again) of spectrum of culprits  Combinations of genes (complex genes – speech and language, social, emotional development)  Certain obnoxious and toxic chemical, viruses, medical conditions in the pregnant mother, or developing child that affect specific areas of the brain at critical periods of development  Stressful environmental circumstances that significantly affect development
  61. 61. Conclusions in Autism Cardinal triad of Language delays, Social aberrancies, and ritualistic, compulsive behavior Neuropsychological deficits  Processing emotional stimuli  Frontal lobe functioning Biochemical abnormalities  Focusing on serotonin and endorphin systems Immune and endocrine dysfunction  Suggestive of autoimmune problems or viral origins Electrophysiological abnormalities  Overall ABNL CNS development  Confounded with ABNL EEG  Abnormalities in limbic processing Imagining and blood flow studies  Overall CNS hypertrophy in early development  Possible programmatic delays and aberrancies Planning Pruning Autopsy studies  Suggesting limbic, frontal cerebellar cellular abnormalities
  62. 62. Savant Skills in Autism Spectrum Disorders •Delopm entsl disorders including Autism, display expertise, ability, or brillaince that contrast with the individual’s overall limitations •10% ASD youngsters show savant traits •Of those with savant traits, 50% display symptoms compbatinlb eith ASD
  63. 63. Neurological Conditions: Autistic behaviors Neurological development disorders – that have Autism as a component  Rett Syndrome MECP2 located on the X chromosome and can arise (1) sporadically or (2) from germline mutations  Neurofibromatosis Neurofibromatosis type 1 - mutation of neurofibromin chromosome 17q11.2 Neurofibromatosis type 2 - mutation of merlin chromosome 22q12  Tuberous Sclerosis mutations on either of two genes, TSC1 and TSC2, which encode for the proteins hamartin and tuberin respectively  Fragile X expansion (excessive repetition) of a single trinucleotide gene sequence (CGG) on the X chromosome, and results in a failure to express the FMR-1 protein
  64. 64. Action Continued study on the genetic, and neurological origins of Autism *Early identification of Autism System of professionals and schools to diagnose Educational and behavioral treatments Genetic counseling (if needed) Supply appropriate medical treatments if needed *Educational and behavioral treatments School systems committed to supplying appropriate resources *Proper prenatal care Education of females on prenatal care Delivery of care *Sensitivity to environmental toxins Clean up these chemicals that cause birth defects and might be related to developmental disorder *Keep open minds about the use of substances such as mercury Maybe a substance that causes autism in a particular very susceptible individual? benefits and risks to society *Strong programs to prevent, and detect child abuse and neglect
  65. 65. Neurological Conditions: Autistic behaviors Neurological development disorders – that have Autism as a component  Rett Syndrome MECP2 located on the X chromosome and can arise (1) sporadically or (2) from germline mutations  Neurofibromatosis Neurofibromatosis type 1 - mutation of neurofibromin chromosome 17q11.2 Neurofibromatosis type 2 - mutation of merlin chromosome 22q12  Tuberous Sclerosis mutations on either of two genes, TSC1 and TSC2, which encode for the proteins hamartin and tuberin respectively  Fragile X expansion (excessive repetition) of a single trinucleotide gene sequence (CGG) on the X chromosome, and results in a failure to express the FMR-1 protein
  66. 66. Psychiatric Diagnoses are Unique Psychiatric, Neuropsychiatry, Mental disorders are different from medical disorders: based on behavior, emotions, cognitions (thinking), movements No ‘consistent’ laboratory test Example: Diabetes: high blood sugar  Urinary frequency  Fatigue  Eye, kidney, heart, other organ systems involvement and observable

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