Autism Spectrum
Disorders
Isabelle Rapin
Seminar on developmental disorders
Child neurology
January 23, 2013
No conflict of interest
Goldman et al. 2009
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
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

Hierarchies: genes to behavior
A. Classification - BEHAVIORAL
– MAINLY DESCRIPTIVE (dimensional)
Living, behaving whole person – many behaviors
B. Mechanisms – BIOLOGIC PATHOPHYSIOLOGY
1.
2.
3.
Brain – molecules, cells, networks
Cells – molecules, networks
Molecules - networks
C. Classification - ETIOLOGY, BIOLOGIC CAUSES –
MAINLY CATEGORICAL (discrete, yes/no)
1.
2.
3.
Genetics
Environment
Both (incl. epigenetics)
Severity: Bell - shaped
at the behavioral level
Behavioral diagnoses = arbitrary cuts in a
continuum  NOT DICHOTOMOUS
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”)
Overlapping syndromes –
One brain !
Etc.
OCD
Autism
Tourette
MR
Learning
disability,
language
disorder,
dyslexia, etc.
ADHD
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
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
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
Genes that influence Type 1A diabetes
New Engl J Med April 16, 2009
One disease –type 1A diabetes: many genes, only one for insulin !
Some of the direct and indirect targets of networks of
differentially methylated and expressed genes
Courtesy Dr. V.W.Hu et al
Genes do not
program
behaviors !
Genes
Cellular metabolic
microcircuitry
Brain
Brain networks
program
behaviors
Anatomo-physiologic
networks
Behaviors
CAVEAT !
Differentiate levels of investigation!
AUTISM SPECTRUM -/- THE AUTISMS
behavioral
biologic
severity
etiologies
dimensional
enumerative
DSM-5 (2013):
Autism Spectrum Disorder (ASD)
1.
Deficient social communication and interaction (all 3)
1.
2.
3.
2.
Restricted repetitive patterns of behavior, interests and
activities (at least 2)
1.
2.
3.
3.
Marked deficit in nonverbal and verbal social communication
Lack of social reciprocity
Poor development and maintenance of peer relationships
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
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
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.
Physical/neurologic features
None 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
Trajectory of brain growth in ASD
(Courchesne et al, 2007)
Selectively affected areas:
Frontal lobe
Temporal lobe
Cerebellum
Amygdala
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
Autism: Hippocampal Neurons
(Bauman & Kemper 1985-1994)
22
Cortical minicolumns in cortical area 4
lamina III in autism vs control brain
Normal
control brain
Casanova
2006
ASD brain
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.
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
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?
Frequent motor findings
 Stereotypies
• motor, +/- object
• behavioral
 Dystonic postures
 Toe walking
 Increased joint laxity (hypotonia)
 Clumsiness
 Dyspraxia
Frequent sensory findings:
hyper- & hypo-sensitivity








Touch
Pain, temperature
Proprioception
Vestibular
Audition
Vision
Taste
Smell
Sleep problems





Difficulty falling asleep
Difficulty staying asleep
Need for less sleep time
Need for excessive sleep
Inadequate circadian entrainment
Levels of language coding (1)
 Phonology – speech sounds
- phonetics…...segmental
- prosody……..suprasegmental
 Grammar −sentence structure
- syntax………..word order
- morphology…word endings, etc.
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
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
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
(62 ASD school-agers)
(M)
(-1 sd)
(-1 sd)
(M)
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 ?
Language regression
(N = 177 children)
Age < 3 years
Age > 3 years
91% autistic
14% seizures
58% autistic
53% seizures
Shinnar et al. 2001
Language Regression
EEG sleep study
(N = 177 children)
Without seizures
With seizures
• 21% EEG abnormal
• 78% EEG abnormal
• 92% autistic
• 69% autistic
(Shinnar et al, 2001)
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
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 ???
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 ???
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
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
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
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
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