Autism

1. Autism Laura Wong Laura.Wong@tufts.edu

2. Take Home Points • Autism (and ASD) is genetically and phenotypically diverse • The unifying feature of the genetic data is that genes involved frequently relate to the synapse which can affect neuronal networks

3. Overview of the clinical features • Current research • Some theories • Possible treatments

4. Overview of the clinical features • Current research • Some theories • Possible treatments

5. A little history • 1943, Leo Kanner • Observed 11 boys • Used term “autism” to describe the progressive loss of contact with outside world • Hans Asperger • Concurrently, and independently wrote thesis on same type of child • Also used “autism”

7. A 7-year-old boy has significant impairment in social interaction, lectures rather than converses, and is obsessed with dinosaurs. His cognitive and language development are age appropriate. The most likely diagnosis is: . • autism. • Asperger's disorder. • social anxiety disorder. • oppositional defiant disorder. • Rett' s disorder

8. A 7-year-old boy has significant impairment in social interaction, lectures rather than converses, and is obsessed with dinosaurs. His cognitive and language development are age appropriate. The most likely diagnosis is: . • autism. • Asperger's disorder. • social anxiety disorder. • oppositional defiant disorder. • Rett' s disorder

9. A 7-year-old child is brought in for an evaluation. The child began using phrase speech at 48 months of age, has poor self-help skills, and has an inability or unwillingness to follow instructions in class. The child does not engage in appropriate eye contact, respond to the social signals of others, nor engage in imaginative play. The child's language is still moderately delayed. The most likely diagnosis is: • childhood schizophrenia. • oppositional deviant disorder. • Asperger's disorder. • Rett syndrome. • autism.

10. A 7-year-old child is brought in for an evaluation. The child began using phrase speech at 48 months of age, has poor self-help skills, and has an inability or unwillingness to follow instructions in class. The child does not engage in appropriate eye contact, respond to the social signals of others, nor engage in imaginative play. The child's language is still moderately delayed. The most likely diagnosis is: • childhood schizophrenia. • oppositional deviant disorder. • Asperger's disorder. • Rett syndrome. • autism.

11. Autism most commonly occurs as a comorbid with which of the following? • Mental retardation • Bipolar affective disorder • Substance use disorder • Obsessive-compulsive disorder • Attention-deficit hyperactivity disorder (ADHD)

12. Autism most commonly occurs as a comorbid with which of the following? • Mental retardation • Bipolar affective disorder • Substance use disorder • Obsessive-compulsive disorder • Attention-deficit hyperactivity disorder (ADHD)

13. From dsm5.org

14. Overview of the clinical features • Current research • Some theories • Possible treatments

15. From Holt and Monaco, 2011

16. Causes: Genetics at the Synapse • Neural migration • Reelin • Neurotrophin family • Synaptogenesis • Neuroligins • Neurexin • Shank3 • Neurotransmission • Serotonin transporter • GABA and glutamate receptors • Voltage-gated ion channels • Each responsible for less then 1% of autism cases Gepner et al 2009

17. Penzes et al 2010

18. Testing Mouse Models of Autism DiCicco et al 2006

19. Autistic Mouse Model: NLGN4 KO Mouse Ultrasonic Communication Mouse Socialization Jamain et al 2005

20. Autistic Mouse Model: NLGN4 KO Jamain et al 2005

21. Shank3 KO

22. Shank3 KO

23. Shank3 KO mouse

24. Problem These mutations account for only a small percentage of autism!!

25. Copy Number Variations • Alterations of genomic DNA structure resulting in the cell having an abnormal number of copies of one or more sections of DNA

27. Duplication of Ube3a Smith et al. 2011

28. Overview of the clinical features • Current research • Some theories • Possible treatments

29. Neuronal Homeostasis From Ramocki and Zoghbi, 2008

30. From Holt and Monaco, 2011

31. Transcriptional Studies Neuronal genes Inflammatory/Immune

34. Overview of the clinical features • Current research • Some theories • Possible treatments

35. Chelation Trial to test use of DMSA (a common chelator) failed to pass IRB due to concerns regarding safety in those without detectable heavy metal poisoning.

36. Minocycline Dendritic spines Ultrasonic Vocalizations Rotschafer S.E, 2012 Bilousova et al, 2009

38. Take Home Points • Autism (and ASD) is genetically and phenotypically diverse • The unifying feature of the genetic data is that genes involved frequently relate to the synapse which can affect neuronal networks

39. Common Traits of Autism • Preference for aloneness • Insistence on sameness • Liking elaborate routines • Some abilities that seemed remarkable compared to deficits

40. Core Domains • Socialization • Impaired use of non-verbal behaviors • Delayed peer interactions • Absence of seeking to share enjoyment and interests • Delayed initiation of interactions • Little or no social reciprocity and absence of social judgment • Communication • Delay in verbal language without non-verbal compensation • Impairment in expressive language and conversation, and disturbance in pragmatic language use • Stereotyped, repetitive, or idiosyncratic language • Delayed imaginative and social imitative play • Behavior • Preoccupation with stereotyped or restricted interests or topics • Adherence to routines and rigidity behavior • Stereotyped, repetitive motor mannerisms • Preoccupation or fascination with parts of items and unusual visual exploration