Autism Spectrum Disorders

1. Autism Spectrum Disorders Isabelle Rapin Seminar on developmental disorders Child neurology January 23, 2013 No conflict of interest

2. Goldman et al. 2009

3. What is autism? (2013) • A developmental behaviorally-defined syndrome/phenotype • Impacts social skills & communication • Associated with narrow, rigid, repetitive behaviors • NOT A “DISEASE” ! • Affects the immature, developing brain

4. Causes of autism • Many genetic influences • in most cases multiple • most with small effects on brain development • Interacting environmental (epigenetic) influences • via their pathophysiologic effects on • molecular networks • cellular networks • brain circuitry

5. Hierarchies: genes to behavior • Classification - BEHAVIORAL – MAINLY DESCRIPTIVE (dimensional) Living, behaving whole person – many behaviors • Mechanisms – BIOLOGIC PATHOPHYSIOLOGY • Brain – molecules, cells, networks • Cells – molecules, networks • Molecules - networks • Classification - ETIOLOGY, BIOLOGIC CAUSES – MAINLY CATEGORICAL (discrete, yes/no) • Genetics • Environment • Both (incl. epigenetics)

6. Severity: Bell - shaped at the behavioral levelBehavioral diagnoses = arbitrary cuts in a continuum NOT DICHOTOMOUS

7. Behavioral classification • Arbitrary cuts in a continuum  • entities with fuzzy margins • entities not either/or (i.e., not discrete, dichotomous) • overlap with “normality” • overlaps with one or more other entities (“co-morbidities”)

8. Overlapping syndromes – One brain ! Etc. OCD Tourette Autism MR ADHD Learning disability, language disorder, dyslexia, etc.

9. Biologic classification • For the most part yes/no (dichotomous) • But: • often many different mutations in a given gene  different phenotypes, severity, penetrance • each gene affects complex molecular/cellular networks • a given network is vulnerable to many different gene mutations • gene expression modified by • genetic background • epigenetic (environmental) influences

10. Early Genetic Evidence • Was 4/10,000 for autistic disorder • Now 1/88 ASD • Recurrence risk: < 10%, thus single mendelian genes rare  mostly multigenic • Multiplex families in Utah (Ritvo 1985-90s) • Male dominance, yet male/male transmission  not often x-linked • Stoppage rule

11. Current Genetic Views • Now known etiologies no longer rejected • Association with known mono-genetic disorders • PKU • Tuberous sclerosis • Fragile-X • Angelman, Cornelia de Lange, etc., etc. • Candidate gene studies • Multiplex families • Linkage studies (cytogenetics, CNVs [microdeletions, duplications, translocations], loci, genes) • Whole genome searches – gwas (genome-wide association studies, microarrays) • mono- vs. heteroallelic expression • multiple genes with small effects vs. single genes with stronger effects

12. Genes that influence Type 1A diabetes New Engl J Med April 16, 2009 One disease –type 1A diabetes: many genes, only one for insulin !

13. Some of the direct and indirect targets of networks of differentially methylated and expressed genes Courtesy Dr. V.W.Hu et al

14. Genes Genes do not program behaviors ! Brain networks program behaviors Cellular metabolic microcircuitry Brain Anatomo-physiologic networks Behaviors CAVEAT !

15. Differentiate levels of investigation! AUTISM SPECTRUM -/- THE AUTISMS behavioral biologic severity etiologies dimensionalenumerative

16. DSM-5 (2013):Autism Spectrum Disorder (ASD) • Deficient social communication and interaction (all 3) • Marked deficit in nonverbal and verbal social communication • Lack of social reciprocity • Poor development and maintenance of peer relationships • Restricted repetitive patterns of behavior, interests and activities (at least 2) • Stereotyped motor or verbal behaviors or unusual sensory behaviors • Excessive routines & ritualized patterns of behavior • Restricted, fixated interests • Clinically significant, persistent, present since early childhood

17. DSM - 5 • Diagnosis: based entirely on behavioral criteria • Encompasses the entire range of severity • Associated symptoms reflect biologic etiologies • irrelevant to a behavioral diagnosis ! • critical to unraveling pathophysiologies (i.e., what other brain/somatic networks are also affected) • critical to optimal management

18. Some Standardized Behavioral Diagnostic Tests • Childhood Autism Rating Scale – CARS (Schopler et al., 1980) • Autism Diagnostic Interview – ADI (Lord et al., 1989) • Autistic Diagnostic Observation Schedule – ADOS (Lord et al., 1989) • Modified Checklist for Autism in Toddlers -- M-CHAT (Robin et al., 1999) • Etc.

19. Physical/neurologic featuresNone present in all cases or required for diagnosis • Abnormal head growth curve • Physical abnormalities/symptoms • Motor findings • Atypical sensory responses • Sleep problems • Language abnormalities • Autistic-language regression • Epilepsy

20. Trajectory of brain growth in ASD(Courchesne et al, 2007) Selectively affected areas: Frontal lobe Temporal lobe Cerebellum Amygdala

21. Neuropathology • 1980: 4 cases with severe MR: cerebellar + other brain abnormalities (Williams et al.) • 1985-2002: Cerebellum + limbic pathology (Bauman and Kemper) • No major brain anomalies/lesions • Loss of Purkinje cells in cerebellar cortex, neurons in deep cerebellar nuclei, inferior olive • Stunted neurons in diencephalon, amygdala • Pathology progressive in adults compared to children? • 1996: brainstem malformation in one case (Rodier et al.) • HOXA1 gene • Thalidomide, valproate toxicity

22. Autism: Hippocampal Neurons(Bauman & Kemper 1985-1994)

23. Cortical minicolumns in cortical area 4 lamina III in autism vs control brain Normal controlbrain Casanova 2006 ASD brain

24. Current emphases • Dysfunctional networks • Cortical neurons (GABA inter-neurons) • White matter networks • Synapses (H. Zogbi, Science, 2003) • Neuro-transmitters/-modulators • Serotonin • Dopamine • Acetylcholine • Glutamate • Oxytocin/vasopressin • Etc.

25. Frequently reported somatic abnormalities • Minor anomalies, dysmorphic features • Many known syndromes/genetic disorders • Middle ear infections,URIs • GI symptoms • Immunologic abnormalities • THEY DO NOT INVALIDATE AN ASD DX • HAVE TO DO WITH BIOLOGIC CAUSES

26. Open questions • Are somatic features symptoms of ASD? • Is ASD ↑ genetic vulnerability to environmental stresses (physical & emotional) ? (e.g., Herbert, 2012) • Optimal physical health is good for all • But to what extent does striving for optimal physical & emotional health (holistic medicine) improve ASD symptoms? • To what extent are ASD symptoms reversible by optimizing health?

27. Frequent motor findings • Stereotypies • motor, +/- object • behavioral • Dystonic postures • Toe walking • Increased joint laxity (hypotonia) • Clumsiness • Dyspraxia

28. Frequent sensory findings:hyper- & hypo-sensitivity • Touch • Pain, temperature • Proprioception • Vestibular • Audition • Vision • Taste • Smell

29. Sleep problems • Difficulty falling asleep • Difficulty staying asleep • Need for less sleep time • Need for excessive sleep • Inadequate circadian entrainment

30. Levels of language coding (1) • Phonology – speech sounds -phonetics…...segmental - prosody……..suprasegmental • Grammar −sentence structure - syntax………..word order - morphology…word endings, etc.

31. Levels of language coding (2) • Semantics – meaning of utterance - lexicon…….word dictionary in brain - meaning of connected speech • Pragmatics – conversational language - verbal………turn taking, referencing, etc. - nonverbal….facial expression, gestures, body posture, prosody

32. Impaired language in autism • At preschool • Comprehension: ~ always impaired • Expression: pragmatics always impaired + • (1) no language / language regression: often presenting sign or • (2) verbiage, echolalia, impaired conversational use (pragmatics) and prosody • At schoolage • More than one subtype of language deficit • Pragmatics impaired life-long

33. Subtypes of dysphasia in ASD • Nonverbal/dysfluent • ↓ phonology, syntax, semantics & pragmatics impaired (impoverished language) • ↓ comprehension, even up to VAA • Verbal, mostly fluent (semantic-pragmatic) • Phonology, syntax OK • Atypical vocabulary; some anomic • ↓ comprehension of discourse (questions) - worse than expression • Impaired pragmatics, conversation, chatterboxes • Atypical prosody, delayed echolalia, perseveration

34. (62 ASD school-agers) (M) (-1 sd) (-1 sd) (M)

35. Language / Autistic Regression • Parents: language/autistic regression in ~ 1/3 of toddlers • Mean age 21 months (~12-36 mos.) • Triggers? • Infectious/immunologic? • Psychological stress? • Improvement but not full recovery • Relation to long-term prognosis ?

36. Age < 3 years 91% autistic 14% seizures Age > 3 years 58% autistic 53% seizures Shinnar et al. 2001 Language regression(N = 177 children)

37. Without seizures 21% EEG abnormal 92% autistic With seizures 78% EEG abnormal 69% autistic (Shinnar et al, 2001) Language RegressionEEG sleep study(N = 177 children)

38. Epilepsy in autism • Related to the severity, location, type of brain pathology/cognitive level • Related to type of language disorder • Rare in high functioning children • Peaks in early childhood and in adolescence • Rarely the cause of autistic regression

39. Autistic Regression and Epilepsy • Relation to Landau-Kleffner syndrome (language regression with either seizures or a subclinical epileptiform EEG)? • Relation to status epilepticus in slow wave sleep (ESES)? • Limited value of all-night EEG monitoring • TO TREAT OR NOT TO TREAT ???

40. Autistic Regression vs Disintegrative Disorder • Heller (1908 & 1930): behavioral and language regression in preschooler/schoolage children, including ADL • Poor prognosis • Heterogeneous disorder (a few degenerative diseases, most not) • Are late autistic regression and DD on a continuum ???

41. ERPs / Imaging • ERPs – oddball method: real time measures of sensory processing  data in the msec. domain • Parcellated morphometry • white matter enlargement in radiate fibers (Herbert) • reversed asymmetry of language areas (also in DLD !) • fMRI to study sensory processing by altered blood flow in activated regions  networks • PET ditto, but also study of metabolism using ligands (e.g., glucose, serotonin, DA, AMPA…) • Diffusion tensor imaging to study connectivity

42. Goals of Intervention • Stop looking for a cure • Stop striving for ‘normality’ • Think adaptation, i.e., fixing, circumventing • Consider the individual’s needs • Tolerate socially acceptable differences • Welcome the unique contributions of some

43. Where to go: biology • Elucidate pathophysiology, i.e., what goes on in the brain (neurotransmitters, neuromodulators, epilepsy, etc…) • Pathophysiology more likely to lead to new drugs than genetics • Elucidate basis of autistic regression • Devise a rational treatment for autistic regression

44. Where to go: genetics • In the clinic: • Limited referral based on family history & phenotype • Probability of a specific genetic diagnosis low • Always discuss recurrence risk ! • Lack of prenatal diagnosis unless etiology known • For research (paid for by research funds !) • Strongly encourage enrollment in a funded comprehensive study, but • ~ never results in specific Rx of child

45. Where to go: medical interventions • Discourage use of medical/dietary treatments that have no reasonable rationale • Urgent need to evaluate efficacy of medical and educational interventions in well studied subgroups of individuals