Autism Spectrum Disorders Isabelle Rapin Seminar on developmental disorders Child neurology January...
-
Upload
giles-harmon -
Category
Documents
-
view
216 -
download
1
Transcript of Autism Spectrum Disorders Isabelle Rapin Seminar on developmental disorders Child neurology January...
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