Lecture 3: ASD Flashcards
Autism Spectrum Disorder
*A neurodevelopmental syndrome
representing a spectrum of impairments
rather than discrete disorders
Definition and prevalence
Definition and prevalence • Persistent deficits in social communication and social interactions • Pattern of restricted and repetitive behaviors • Impairment in multiple settings socials, educational, occupational functioning • Onset in early childhood (mean: 66.36 months; age 5) • ~5 times more often in boys than girls • 1 in 68 children, USA • Prevalence varies cross-culturally
*Boys > Girls
Comorbidity (associated deficits)
ASD
• Children with ASD often present with: o Intellectual impairment o Language impairment o Motor deficits o Poor adaptive behavior o Medical problems • Children with ASD often have behavioural problems: o Aggressiveness o Hyperactivity o Impulsivity o Attention problems o Self-injurious behavior
Comorbidity
• In general, ASD follows a continuous
course but depending on intelligence level
and language skills, developmental gains
are possible during school-age years
• A minority of individuals with ASD live and
work independently
• Early intervention and structured
behavioural support programs can enhance
the functioning of children in later life; ASD
individuals with the higher language and
intellectual abilities have a greater
likelihood of living independently.
Savants
• In rare cases children with ASD can have
exceptional skills known as savant talents:
o Music
o Memory
o Mathematics
o Specific knowledge
o Art
• Rare cases (one in ten individuals with ASD)
Reading:
- Savant skills: (a) are accompanied with at
least an average level intelligence; (b) skills
are similar to those without ASD.
Genetics
*Genes play a major role in the
development of ASD
Family and twin studies
Family and twin studies
• Having at least one older sibling with ASD
increases the risk of the disorder in
younger siblings by 18.7%
o Considerably higher than previous
estimates of 3% to 10%
o Higher risk in younger male siblings
relative to female (26% vs 9%)
• Risk of ASD 33% to 50% if two or more
siblings have the disorder
• First degree relatives of ASD individuals
have increased behavioural and cognitive
symptoms (i.e., social communication
problems)
• Higher rates for monozygotic (identical)
than dizygotic twins (i.e., heritability
estimates; 0.64- 0.91 vs. 0.18-0.34)
Linkage studies and candidate genes
Majority of cases are…
Do they have an identifiable genetic condition?
Gene variation?
Linkage studies and candidate genes
• Majority of cases of ASD are idiopathic
(spontaneous with an unknown cause)
• ~10% have an identifiable genetic condition
• Fragile X syndrome
• Tuberous sclerosis
• Prader Willi syndrome
Genetics
• Substantial genetic heterogeneity in ASD
o Genes may be different for every individual
o May involve many genes (10-100s)
o May interact with environmental factors
• Chromosomal abnormalities involving
nearly every chromosome have been linked
to ASD
o Chromosomal duplications
o Inversions
o Terminal and interstitial deletions
o Translocations
• Over 1,000 genes have been linked to ASD
Linkage and Genome Studies
Genetics (GABA)
Genetics (GABA) • Variants of the GABRA4 gene (chromosome 4) and GABRB3 gene (chromosome 15) • These genes encode a protein that is part of the GABA receptor which plays an important role in neuronal inhibition. • GABRB3 gene is a focus of ASD research because individuals with Prader-Willi syndrome and Angelman’s syndrome (caused by abnormalities of chromosome 15) tend to have coexisting ASD.
*For Autism they tend to say coexisting
instead of comorbidity
Linkage and Genome Studies
Oxytocin receptor gene (OXTR)
Oxytocin receptor gene (OXTR)
• OXTR gene (chromosome 20) is implicated
in the production of oxytocin (love drug) that
is involved in social bonding and affiliative
behaviour.
• It has been studied in relation to ASD due
to their deficits in social bonding and
affiliation deficits.
• Four polymorphisms in OXTR gene are
associated with differences in amygdala
volume and white matter connectivity in
ASD.
Linkage and Genome Studies
RELN gene
RELN gene
• RELN gene is located on chromosome 7
and provides instruction for the production
of reelin. It is thought to play a critical role in
cell migration and neuroplasticity during
development.
• Polymorphisms of RELN gene (rs362691)
are associated with increased risk of ASD.
•.More than 40% reduction of reelin protein
in ASD postmortem samples.
• A single mutation of the RELN gene can
result in reduced reelin production, cellular
function and neuroplasticity during
development.
• RELN mutations are 4x more likely in males
than females
Linkage and Genome Studies
SHANK3 gene
SHANK3 gene
• Located on chromosome 22 and provides
instructions to make the protein proline-rich
synapse-associated protein that plays a
critical role in the formation of dendritic
spines and in synaptic connections.
• Mutations of SHANK3 gene linked to ASD
(mixed)
Linkage and Genome Studies
Other genes
Other genes • Serotonin transporter gene (SLC6A4) • N-methyl-D-aspartate receptor gene (NMDA, GRIN2B) • Arginine vasopressin receptor 1A gene (AVPR1A) • Engrailed homeobox 2 (EN2) • Integrin, beta 3 (platelet glycoprotein IIIa, antigen CD61; ITGB3) • Met proto-oncogene (hepatocyte growth factor receptor; MET) • Contactin-associated protein-like 2 (CNTCAP2)
Environment
• Research in its infancy, speculate stress
and other factors influence cellular
functioning (epigenetics; how environment
influences gene expression)
Structural findings
• Differences in total brain volume, volume of
specific structures, gray and white matter,
cortical thickness/thinning, and more
connectivity between structures and brain
regions:
o ~20% of individuals with ASD have
unusually large head circumference
o ~15% of individuals with ASD have
unusually small head circumference
o Enlarged brain volume (macroencephaly is
more common in low functioning ASD and
in younger but not older children)
o Brain volume normal at birth; however, by
ages 2-4 years, 90% of boys with ASD have
greater than average brain size
o Concomitant regional volume differences in
the frontal and temporal (increase) lobes
o Reduced cortical thickness in temporal
cortex
o Increased cortical thickness in frontal
cortex
o Fewer neurons
o Smaller neurons
o Smaller receptor densities in cerebellum,
frontal and temporal cortex
- Smaller subcortical volumes
- Pallidum
- Putamen
- Amygdala
- Nucleus accumbens
- Corpus callosum
o Enlargement of the caudate nucleus
(enlargement is associated with increased
symptom severity and restrictive/repetitive
behaviours)
*Structural cellular differences believed to be
caused by problems with neural migration
and connectivity in individuals with ASD
*Abnormal brain development in ASD within
the frontal, parietal, and subcortical
structures. These are involved in language,
social perception, self-referential, and self-
regulation.
White matter
• ASD is associated with gray matter
reductions, excess white matter, and
widespread compromised integrity of white
matter tracts throughout the brain.
• E.g., abnormalities of white matter tracts
connecting the right amygdala to the right
cortex (is associated with the severity of
emotional recognition deficits in ASD)
Interpretation of results
• Not all studies find morphological
differences in ASD
• Most of the identified morphological
differences are not unique to ASD
o E.g., cortical thinning, reduced gray/white
matter, impaired white matter integrity,
enlarged caudate have been seen in
schizophrenia, anxiety disorders, OCD,
ADHD, bipolar disorder, and Tourettes.
o Support vector models can be used to
discriminate morphological differences
between ASD and other disorders or
controls (e.g., in infants at risk of ASD)
ASD brain bank
• Neuroimaging studies lack the resolution
needed to examine cellular and molecular
changes associated with ASD. Postmortems
of high-quality ASD brain tissue is needed.
• To support the collection of high-quality
brain tissue, ASD brain back was developed - a privately funded network of brain tissue
collection
• Strict procedures for collecting, preparing,
and preserving human brain donations
• Autism Brain Net (autismbrainnet.org)
*Structural findings are correlational! We don’t
know whether morphological differences
cause symptoms or vice versa.
