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

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 PATHOPHYSIOLOGY1. Brain – molecules, cells, networks2. Cells – molecules, networks3. Molecules - networks

C. Classification - ETIOLOGY, BIOLOGIC CAUSES – MAINLY CATEGORICAL (discrete, yes/no)

1. Genetics2. Environment3. 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 !

Autism

OCDOCD

MRMR

Learning Learning disabilitydisability, , language language disorder, disorder, dyslexia, etc.dyslexia, etc.

TouretteTourette

ADHDADHD

Etc.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

Brain

Behaviors

Genes do not program behaviors !

Brain networks program behaviors

Cellular metabolic microcircuitry

Anatomo-physiologic networks

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 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

Trajectory of brain growth in ASD(Courchesne et al, 2007)

Selectively affected areasSelectively affected areas::

Frontal lobeFrontal lobe

Temporal lobeTemporal lobe

CerebellumCerebellum

AmygdalaAmygdala

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)

Cortical minicolumns in cortical area 4 lamina III in autism vs control brain

Normal control brain

ASD brainCasanova

2006

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 abnormalitiesTHEY DO NOT INVALIDATE AN ASD DXHAVE 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

91% autistic14% seizures

Age > 3 years

58% autistic53% seizures

Shinnar et al. 2001

Language Regression

EEG sleep study (N = 177 children)

Without seizures

• 21% EEG abnormal

• 92% autistic

With seizures

• 78% EEG abnormal

• 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