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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. 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
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
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
Brain
behaviors
Behaviors
CAVEAT !
Differentiate levels of investigation!
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)
(M)
(-1 sd)