Autism:

Spectrum Disorders
 What is autism?
▪ A developmental behaviorally-defined
syndrome/phenotype
• Impacts social skills & communication
• Associated with narrow, rigid, repetitive
behaviors
▪ NOT A “DISEASE” !
▪ Affects the immature, developing brain
 What is autism?
• Autism is a ‘hidden disability’, meaning it is not easy to recognize when
someone has the condition.
• When you see the following pattern (on a wristband, card or mobile
device) it means someone has autism and wants you to know so that you
can support them:

• Autistic people often have difficulty in accessing community activities,

leisure facilities, and other services.
• Everyone having a better understanding of autism has the power to
change lives.
• The following information is provided to help you to gain a better
understanding of autism and suggests ways in which you can support
autistic people.

For more information on the ‘Can You See Me?’ scheme, please visit:
https://www.asdinfowales.co.uk/can-you-see-me
 What is autism?
Autism is also known by other names, including:

Autism Spectrum
Disorder (ASD) Asperger’s
Syndrome

Autistic Spectrum
Condition (ASC) Pervasive
Developmental
Disorder
 What is autism?
Autism is a lifelong condition and
affects people from all backgrounds.
Currently more males than females
are diagnosed with autism.
It is estimated that 1 in every 100 people in the
UK have an Autism Spectrum Disorder (ASD).
Many people are unaware that they are autistic.
This is especially true for adults.
 What is autism?
Autistic people have differences in the following
areas:

Social Imagination and

Social Communication &
Flexibility of Thought
Social Interaction

Restricted, repetitive Restricted, repetitive Unusual sensory

interests or activities patterns of behaviour responses
 What is autism?
Autistic people experience social communication differences.
The way this affects a person can vary, and can include difference in
the use and understanding of:

speech language
gestures
tone of
eye contact voice
Social Communication & Social Interaction

How this impacts on day to day life:

People often use body language

and sarcasm to convey
something. Autistic people may be Their tone of voice may not
perceived as rude because they always reflect the way an
avoid eye contact. autistic person is feeling.
Autistic people often find these
difficult to understand.

Autistic people may interpret

An autistic person may not be language literally and so may
able to use gestures or interpret misunderstand idioms (“pull
other people’s gestures. your socks up”) and metaphors
(“my head was spinning”).
Social Communication & Social Interaction

Autistic people experience social interaction differences.

The way this affects a person can vary, and can include difference in
the use and understanding of:
engaging in
building and sustaining conversation
relationships
understanding
giving and receiving humour
compliments

showing concern for others

Social Communication & Social Interaction

How this impacts on day to day life:

Developing and maintaining

Autistic children may find it
difficult to instigate or join in play
with other children.
Autistic children may find it
difficult to take turns and share.
This can cause problems with
friendships.
friendships and relationships can
be difficult for everyone.
Autistic adults have told us that
they find this particularly difficult.
This does not mean that they do
not want relationships and
friends.

Autistic people may not engage in

Autistic people may have
conversation in the same way, and
difficulty in understanding the
enjoy discussing factual issues
rules of social relationships.
rather than small talk.
This may cause many issues
You may have to be specific when
including them offering truthful
you want to bring the
opinion rather than a tactful one.
conversation to end.
Social Communication & Social Interaction
Autistic people experience social imagination differences.
The way this affects a person can vary, and can include
difference in the use and understanding of:

predicting reactions problem

and events solving

relating to coping with

others changes

planning
Social Imagination and Flexibility of Thought

How this impacts on day to day life:

Playing team games often relies

When problem solving, we rely Autistic people may find it
on social imagination to predict
on our social imagination to difficult to predict how others
how other people will interact
predict possible outcomes. may be feeling or how they will
in the game.
This is difficult for an autistic react due to problems with
This can be difficult for autistic social imagination.
person.
people.

Some autistic people have

difficulties with creative
imagination.
Others have good creative
imagination, and only the social
imagination is affected.
Planning can be difficult
without good social
imagination, autistic people
often use calendars or planners
to help them with this.
Coping with changes can be
difficult without good social
imagination.
Autistic people usually prefer
routines to unpredictability.
Unusual Sensory Responses

Many autistic people can have sensory issues.

The person’s perception of the senses can be heightened or
decreased. All the senses can be affected.

tactile • (touch)
vestibular • (movement)
proprioceptive • (body position)
visual • (looking)
auditory • (hearing)
olfactory • (smell)

gustatory • (taste)
Unusual Sensory Responses
How this impacts on day to day life, both positively and
negatively:

Sensory joy from certain Sensory joy from the feel of

colours certain materials – Decreased feelings of pain
“stimming”

Sensitivity to lighting in Difficulties around noisy

Dislike of certain colours
shops traffic

Inability to tolerate certain Distress/anxiety in busy

Sensitivity to touch
smells environments
Adapt Your Communication

Communication - adapting your communication can help an

autistic person:

Avoid
Allow time relying on
Speak for the gesture,
slowly and person to facial
clearly process expression
information or tone of
voice

Don’t use Keep

idioms or instructions
metaphors short
 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. Brain – molecules, cells, networks
2. Cells – molecules, networks
3. Molecules - networks
C. Classification - ETIOLOGY, BIOLOGIC CAUSES –
MAINLY CATEGORICAL (discrete, yes/no)
1. Genetics
2. Environment
3. 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

Tourette
Autism
MR

ADHD
Learning
disability,
language
disorder,
dyslexia, etc.
 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
Genes do not
program
Cellular metabolic
behaviors ! microcircuitry

Brain

Brain networks Anatomo-physiologic

program networks

behaviors
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. Marked deficit in nonverbal and verbal social communication
2. Lack of social reciprocity
3. Poor development and maintenance of peer relationships
2. Restricted repetitive patterns of behavior, interests and
activities (at least 2)
1. Stereotyped motor or verbal behaviors or unusual sensory behaviors
2. Excessive routines & ritualized patterns of behavior
3. Restricted, fixated interests
3. 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)

34
 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 58% autistic

14% seizures 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