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Autism Spectrum Disorders

Autism Spectrum Disorders. Neurodevelopmental disorders characterized by qualitative abnormalities in social/emotional behavior and communication as well as restricted, stereotyped and repetitive interests or activities. Autism Spectrum Disorders. Learning Objectives Symptomology

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Autism Spectrum Disorders

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  1. Autism Spectrum Disorders Neurodevelopmental disorders characterized by qualitative abnormalities in social/emotional behavior and communication as well as restricted, stereotyped and repetitive interests or activities

  2. Autism Spectrum Disorders Learning Objectives • Symptomology • Likely/Unlikely Causes • genetic & environmental • Neuropathology • Screening/Diagnostic Tools • Treatments • educational • medical • CAM

  3. Autism Spectrum Disorders • ASDs differ by: • when the symptoms started • symptom severity • nature of the symptoms • ASDs include: • Autism Disorder (AD) • Asperger’s syndrome (AS) • Pervasive developmental disorder, not otherwise specified (PDD-NOS)

  4. Autism • Descriptions of “autistic-like” behavior date back to the 18th century. • Was first identified as autism by Leo Kanner (1943). • describing 11 children • social aloofness • elaborate repetitive routines • Greek word…autos….meaning “self”, • extrapolated to mean “alone, pre-occupied with self, a withdrawal into private [world]”

  5. Autism -- DSM IV-TR A. Six or more items from the following : 1. Qualitative impairment in social interaction (at least 2) 2. Qualitative impairment in communication (at least 1) 3. Restricted, repetitive & stereotyped patterns of behavior, interests, & activities (at least 1)

  6. Autism -- DSM IV-TR B. Delay or abnormal functioning in at least 1 of the following with onset before 3yo: 1. Social interaction 2. Language used in social communication 3. Symbolic or imaginative play C. Disturbance not better accounted for by Rett’s disorder or Childhood Disintegrative disorder

  7. Autism -- Symptoms

  8. Autistic Disorder -- DSM V • “Autistic Disorder” … now to include the previous separate diagnoses: • Autism • Asperger Syndrome • PDD-NOS • Child disintegrative disorder To ensure that etiology is indicated, where known, clinicians will be encouraged to utilize the specifier:  “associated with known medical disorder or genetic condition.”

  9. Autistic Disorder -- DSM V Must meet criteria 1, 2, and 3: • Clinically significant, persistent deficits in social communication and interactions, as manifest by all of the following: • Marked deficits in nonverbal and verbal communication used for social interaction: • Lack of social reciprocity; • Failure to develop and maintain peer relationships appropriate to developmental level

  10. Autistic Disorder -- DSM V Must meet criteria 1, 2, and 3: • Restricted, repetitive patterns of behavior, interests, and activities, as manifested by at least TWO of the following: • Stereotyped motor or verbal behaviors, or unusual sensory behaviors • Excessive adherence to routines and ritualized patterns of behavior • Restricted, fixated interests • Symptoms must be present in early childhood (but may not become fully manifest until social demands exceed limited capacities)

  11. ASD -- Prevalence • Four times more likely in males • CDC estimates 1 in 110 (0.9%) individuals have an ASD (using data from 2006) Every hour in the United States, three children are diagnosed with autism

  12. ASD -- Prevalence • Increased prevalence can be partially accounted for by: • broadening of diagnostic criteria (~40%) • Charman et al. report that “our prevalence estimates varied by up to 4.5 times from the strictest to the least demanding set of diagnostic criteria.” Int J Epidemiol. 2009 Oct;38(5):1234-8 •  parental age (~11%) •  awareness by parents (social influence)

  13. ASD -- Causes • Multifactoral • Genetic (primarily) • Environmental factors (lesser extent) Pardo, C.A and Eberhart, C.G. Brain Pathol. 2007;17:434-447.

  14. ASD -- Causes • Comorbidity -- Medical condition or syndrome • Epilepsy  30% • Fragile X syndrome  2-5% (25-37% have ASD) • Tuberous sclerosis  3-4% (16-65% have ASD) • Angelman syndrome  1-4% (42% have ASD) • Metabolic diseases  ~5% (46-75% SLO have ASD) • ADHD  2.7% (41% have ASD) • Prader-Willi (25% have ASD) • DiGeorge/velocardiofacial syndrome (34-50%) 10-15%

  15. ASD -- Causes • GENETICS -- Family studies ... if one is AD • Identical twins  60-96% chance the other has AD • Fraternal twins  up to 24% chance the other has AD • Siblings  5-10% chance the others have AD Boyle C, Van Naarden Braun K, Yeargin-Allsopp M. The Prevalence and the Genetic Epidemiology of Developmental Disabilities. In: Genetics of Developmental Disabilities. Merlin Butler and John Meany eds. 2005

  16. ASD -- Causes • GENETICS -- Chromosomal studies • Chromosome 1 – ATP1A2 (seizure susceptibility locus); 1q21.1 deletion, RIMS3 • Chromosome 2 – NRXN1 & DLX1&2 (control early growth & development), GAD1 (2q31), terminal deletion 2q37 • Chromosome 3 – CNTN4, OXTR • Chromosome 4 – GABRA4, GABRB1

  17. ASD -- Causes • GENETICS -- Chromosomal studies • Chromosome 5 – may account for up to 15% • 5p14.1 -- between cadherin 10 and cadherin 9 (cell adhesion) • 5p15 -- SEMA5A (axonal guidance during development) • Chromosome 6 – GRIK2 • Chromosome 7 – RELN, CNTNAP2 (language), MET, EN2 • Chromosome 8 – MCPH1 (speech delay, LD)

  18. ASD -- Causes • GENETICS -- Chromosomal studies • Chromosome 9 – TSC1 • Chromosome 10 – PTEN (may account for ~4.2% ASD), LRRTM3 • Chromosome 11 – DHCR7 • Chromosome 12 – CACNA1C, AVPR1A • Chromosome 13 – NBea (important in brain development) • Chromosome 14 – MDGA2

  19. ASD -- Causes • GENETICS -- Chromosomal studies • Chromosome 15 – maternal duplication of q11-q13 – UBE3A gene (1-3% ASD), GABRB3 • Chromosome 16 – duplication/deletion of a small area involving ~25 genes (1% ASD) N Engl J Med. 2008. 14;358(7):737-9 however, see Eur J Med Genet. 2009 • Chromosome 17 – duplication or deletion (resulting in language problems and obsessive traits) … maybe male only; BZRAP1 • Chromosome 18 – DSC1, DSC2 • Chromosome 19 – TLE2, TLE6

  20. ASD -- Causes • GENETICS -- Chromosomal studies • Chromosome 20 – ADA • Chromosome 21 – NCAM2, GRIK1 • Chromosome 22– deletion @ 22q13.3 (SHANK3) • Chromosome X – originally thought because of 4:1 male to female ASD occurrence • There is no major X-linked gene conferring susceptibility to ASD Am J Med Genet B Neuropsychiatr Genet 2008; 147B(6):830-5 • NLGN3, NLGN4, MeCP2 (duplication),FMR1

  21. ASD -- Causes • GENETICS -- Chromosomal studies • unbalanced chromosome rearrangements and or translocations • duplications or deletions • copy number variants of genes

  22. ASD -- Causes • Maternal Factors • Autoimmune factors • Maternal auto-antibodies interact with fetal CNS proteins Brain Behav. Immun. 2007. 21:351-357; Neurotoxicology. 2008. 29:226-31 • 16% of mothers of AD children have an autoimmune disorder (compared to 2% of the mothers of “normals” • 46% ASD patients have 2 family members with autoimmune disorders J. Child Neurol. 1999. 14:388-394 • More family members = greater risk of ASD • rheumatoid arthritis (70%), celiac disease (3x), type 1 diabetes (1.8x)

  23. ASD -- Causes • Maternal Factors -- prenatal toxins/infection • Thalidomide exposure (20-24d gestation … around the time of the neural tube closure) • Misoprostol exposure (6w gestation) • Valproic acid exposure (probably 20-24d gestation • Chlorpyrifos exposure • Ethanol exposure (possibly 3-5 weeks gestation) … ~2% FAS children have ASD • Rubella exposure (first 8w)

  24. ASD -- Causes • Neuroimmunological • Up to 60% of ASD patients have some type of systemic immune dysfunction. Brain Pathol. 2007;17:434-447. • Post-mortem brain tissues show active and ongoing neuroinflammatory processes • cerebral cortex, white matter and cerebellum. Ann. Neurol. 2005. 57:67-81. • CSF exhibited a proinflammatory profile of cytokines. Ann. Neurol. 2005. 57:67-81. • Advanced glycation end products (AGEs) are elevated in both the brain tissue and serum of autistic patients. NeurosciLett. 2006. 410:169–173.

  25. ASD -- Causes • MMR vaccine • 1998, a study suggested a connection between MMR vaccine and autism Lancet. 1998 . 351(9103):637-41. • MMR  bowel problems  autism • The study had limitations: • small sample size (n=12) • in some of the children symptoms of autism appeared before symptoms of bowel disease • In 2004, 10 of 12 authors retracted. Lancet. 2004 363(9411):750.

  26. ASD -- Causes • MMR vaccine (no association) • Larger studies found no relationship between MMR vaccine and autism. • One of the first population studies found: Lancet. 1999. 353(9169):2026-9 • No  in diagnosis with the intro of MMR • Age of diagnosis was the same in vaccinated vs unvaccinated children • The onset of "regressive" symptoms did not occur within 2 or 4 months of MMR • Ecological studies found lack of association. • BMJ 2001. 322:460–463 (UK), J. Child Psychol. Psychiatry. 2005. 46:572–579 (Japan), Pediatrics. 2006. 118(1):e139-50 (CAN), N. Engl. J. Med. 2002. 347:1477–1482 (Denmark), JAMA 2001. 285:1183–1185 (CA), Pediatrics. 2004. 113:259–266 (GA)

  27. ASD -- Causes • MMR vaccine (no association) • Larger studies found no relationship between MMR vaccine and autism. Fombonne, E. et al. Pediatrics 2006;118:e139-e150

  28. ASD -- Causes • MMR vaccine (no association) • Larger studies found no relationship between MMR vaccine and autism. • 2008 study replicated the original 1998 study with more subjects (25 ASD w GI problems, 13 controls w GI problems) and used one of the original labs for analysis • No difference in presence of MV RNA between groups • Found evidence AGAINST association of autism with MMR exposure. PLoS ONE 2008: 3(9):e3140.

  29. ASD -- Causes • MMR vaccine (no association) • 2010 UK's General Medical Council on Wakefield: • Behaved "dishonestly and irresponsibly" in his research • Unqualified to be carrying out some of the exp. • colonoscopies and lumbar punctures • Unethical when he paid children £5 for their blood samples at his son's b-day party. • “serious professional misconduct” when he filed for a patent on a "safer" vaccine that he was hoping to sell after he discredited the MMR vaccine.

  30. ASD -- Causes

  31. ASD -- Causes • Toxins • Mercury in vaccines (thimerosal) • Thimerosal is 49.6% ethylmercury by weight. • 1999  infants at 6mo were exposed to potentially unsafe cumulative doses of ethylmercury • Due to addition of Hib and HepB vaccines (1991) • 2001  thimerosal was excluded from all vaccines (except some seasonal flu vaccines)

  32. ASD -- Causes • Toxins • Mercury in vaccines (thimerosal) – no association • 2006  an ecological study in Montreal found that the prevalence AD (no thimerosal) was significantly > the prevalence AD (thimerosal)Pediatrics. 118: e139–e150 • Controlled observational studies have not found an association between thimerosal and autismJAMA. 2003. 290:1763–1766 (Denmark), Pediatrics. 2004. 114:584–591 (UK), Pediatrics. 2003. 112:1039–1048 & Arch Gen Psychiatry 2008;65:19-24 (US)

  33. ASD -- Causes • Toxins • Mercury in vaccines (thimerosal) – no association Thimerosal removed from vaccines Schechter, R. et al. Arch Gen Psychiatry 2008;65:19-24.

  34. ASD -- Causes • Toxins • Mercury in vaccines (thimerosal) – no association • Institute of Medicine (IOM) concluded "the evidence favors rejection of a causal relationship between thimerosal-containing vaccines and autism." Immunization Safety Review: Vaccines and Autism, 2004.

  35. ASD -- Risk Factors • Parental age • Mothers … 10y increase  38% increase • Fathers … 10y increase  22% increase • Low birth weight/gestational age • Intrapartum hypoxia • Maternal smoking • Prenatal stress ??

  36. ASD -- Neuropathology

  37. ASD -- Neuropathology • Morphometric – brain size (measured by head circumference) is  ~10% initially Courchesne E., et al. 2003; JAMA 290, 337–344. Courchesne E., et al. CurrOpin Neurol. 2004;17(4):489-496

  38. ASD -- Neuropathology • Brain Bank • Brain size is still 1-3% increased in adulthood. Redcay E and Courchesne E. 2005; Biol. Psychiatry 58, 1–9.

  39. ASD -- Neuropathology • Brain Bank • Abnormalities in frontal and temporal lobe cortical minicolumns (neurons are arranged like beads on a string & believed to comprise the smallest level of functional organization in the cerebral cortex) CONTROL = 10 AUTISTIC = 12 Picket, J. and London, E. J. Neuropathol. Exp. Neurol. 2005;64(11):925-935

  40. ASD -- Neuropathology • Brain Bank • Abnormal maturation of the limbic system ( cell size,  number and density and  neuropil complexity) • hippocampus, subiculum and amygdala •  number of Purkinje and granular cells in the cerebellum • Brainstem abnormalities and neocortical malformations (e.g. heterotopias)

  41. ASD -- Neuropathology • Brain Bank • GAD67 mRNA expression is  40% in cerebellar Purkinje cells of autistic individuals compared to controls Yip, J. et al. ActaNeuropathol. 2007;113(5):559-568

  42. ASD -- Neuropathology • MRI •  brain volume (age related) • Abnormalities in sulcal and gyral anatomy •  size of corpus callosum Biol Psychiatry. 2006. 60: 218–225 Courchesne E., et al. Neurol. 2004;57(2):245-254

  43. ASD -- Neuropathology • MRI • Regional gray & white matter volumetric differences in frontal, parietal & temporal lobes. Courchesne E., et al. CurrOpin Neurol. 2004;17(4):489-496

  44. ASD -- Neuropathology • MRI • Regional gray & white matter volumetric differences in cerebellum (Vermis ) Courchesne E., et al. Neurol. 2001;57(2):245-254

  45. ASD -- Neuropathology • fMRI • Hypoactivation of the fusiform gyrus in face-recognition tasks • Hypoactivation in “social” based cognitive and perceptual tasks DiCicco-Bloom, E. et al. J. Neurosci. 2006;26:6897-6906

  46. ASD -- Neuropathology • PET • Developmental changes in brain serotonin synthesis capacity is dramatically different Autistic Normal Chugani, D.C. et al. Ann. Neurol. 1999;45:287–295

  47. ASD – Screening & Diagnosis Johnson, C. P. et al. Pediatrics 2007;120:1183-1215

  48. ASD – Screening & Diagnosis • 2-level Screening Approach: • At well-baby check-up if fail routine developmental screening: • Infant-Toddler Checklist (from CSBS-DP) 6-24mo • Checklist for Autism in Toddlers (CHAT) 18-24+mo • Modified CHAT (M-CHAT) 16-48mo • Screening Tool for Autism in Two-Year-Olds (STAT) 24-36mo • Social Communication Questionnaire 4yo

  49. ASD – Screening & Diagnosis • Modified Checklist for Autism in Toddlers(M-CHAT) • Parent questionnaire • First 9 questions of CHAT plus 14 more: • 2. Does your child take an interest in other children? • 7. Does your child ever use his/her index finger to point, to indicate interest in something? • 9. Does your child ever bring objects over to you (parent) to show you something?

  50. ASD – Screening & Diagnosis • Modified Checklist for Autism in Toddlers(M-CHAT) • First 9 questions of CHAT plus 14 more: • 13. Does your child imitate you? (e.g., you make a face-will your child imitate it?) • 14. Does your child respond to his/her name when you call? • 15. If you point at a toy across the room, does your child look at it? • Moderate sensitivity, high specificity

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