Transcript Document

Autism
A spectrum of neuropsychiatric disorders characterized by
deficits in social interaction and communication, and unusual
and repetitive behavior.
http://www.medterms.com/script/main/art.asp?articlekey=2399
Autism is a Pervasive Developmental Disorder (PDD)
Who, what, when where why?
The human brain-normal and abnormal development
Genetics
Language and cognition
Social implications
Interventions and therapies
What is a developmental disorder/disability?
Birth defects
-Spina bifida
-Heart defects
-Cleft palate/club foot
-Tay Sachs disease
Developmental Disabilities
-Cerebral palsy
-Down’s syndrome
-Learning disabilities and ADHD
-Autism and PDDs
Pervasive developmental disorders
a group of disorders that are characterized by : impairments in social
interaction, impairment in verbal and nonverbal communication, and a restrictive,
stereotypic pattern of behaviours www.oafccd.com/factshee/fact59.htm
Autism
PDD-NOS
Asperger’s
Rett’s Syndrome
Childhood disintegrative disorder
Characteristics of Autism (1)
-Impaired socia l interactions
-Socia l aloneness that is distinct fro m sh yness
-Impaired communication, symbolic play
-Repetit ive, stereotyped behaviors
examples: hand flapping, turning, stacking objects
-Restricted interests and activiti es (singlemindedness)
-Lack of common sense
-Insistence on sameness
-Spotty intellectual achievements
-Diffi culties with symbolization and abstractio n
Characteristics of Autism (2)
-Dela ys p resent before age 3
-More prevalent in boys
-Often associated with mental re tardatio n
-Associated with other disorders- notably epilepsy
-Diagnosis is based on behavioral tests!
DSM-IV Criteria for Autistic Disorder
Diagnostic and Statistical Manual of Mental Disorders, 4th editio n,
1994, Washin gton, DC: A merican Psychiatric Association, pp. 7071.
A. A total of at least six it ems from (1), (2), and (3), with
at least two from (1), and one each from (2) and (3):
(1) Qualitative impairment in social interaction, as
manifested by at least two of the following:
(a) Marked impairment in the use of multiple
nonverbal behaviors such as eye-to-eye gaze,
facial expression, body postures, and gestures to
regulate social interaction;
(b) Failure to develop peer relationships
appropriate to developmental level;
(c) Markedly impaired expression of pleasure in
other peopleÕshappiness;
(d) Lack of social or emotional reciprocity.
DSM-IV Criteria for Autistic Disorder
(2) Qualitative impairments in communication as
manifested by at least one of the following:
(a) Delay in, or total lack of, the development of
spoken language (not accompanied by an attempt
to compensate through alternative modes of
communication such as gestures or mime);
(b) In individuals with adequate speech, marked
impairment in the abilit y to initiate or sustain a
conversation with others;
(c) Stereotyped and repetitiv e use of language or
idiosyncratic language;
(d) Lack of varied spontaneous make-believe play or
social imitative play appropriate to
developmental level.
DSM-IV Criteria for Autistic Disorder
(3) Restricted repetitive and stereotyped patterns of
behavior, interests, and activities, as manifested by at
least one of the following:
(a) Encompassing preoccupation with one or more
stereotyped and restricted patterns of interest that
is abnormal either in intensity or focus;
(b) Apparently compulsive adherence to specific
nonfunctional routines or rituals;
(c) Stereotyped and repetitiv e motor mannerisms
(e.g. hand or finger flapping or twisting, or
complex whole-body movements);
(d) Persistent preoccupation with parts of objects.
DSM-IV Criteria for Autistic Disorder
B. Delays or abnormal functioning in at least one of the
following areas, with onset prior to age 3 years; (1)
social interaction, (2) language as used in social
communication, or (3) symbolic or imaginative play.
C. Not better accounted for by RettÕs Disorder of
Childhood Disintegrative Disorder.
A little history…
First reports: Leo Kanner (1943), Hans Asperger (1944)
-Impairments in social interactions
-Resistance to changes
-Oversensiti vity to some s timuli (sound)
Aspects of the original report that have been refuted
-Parent were successful educatio nally or professio nally
-Problems relatio nships between parent and children
(Refrig erator mothers!)
-Not rela ted to other medical conditions
-No mental retardatio n
A little history…
1950s- Autism is an early form of schizophrenia
-In 1971 Kolvin demonstrated a bim odal onset among a lar ge
group of ÒpsychoticÓ children- early onset in 1-2 years, la ter
onset after many years of normal behavior
-Early onset showed impairments in social, cogniti ve and
language (autism-lik e), no increased schizophrenia in families
-Later onset showed delusio ns, hallu cinatio ns a nd other features
of schizophrenia
-Autis m diff ered from s chizophrenia in tim e of onset, clinical
features, course, outcome a nd family history
Epidemiology of autism
-First epidemiolo gical studies in England in the 1960s
-Since then more than 30 studies in many countries
-All have used a definiti on of autism that inclu ded severe
impairment in communicatio n, language, social
interactions, play and behavior
-BUT- the crit eria for autism diagnosis has changed over tim e
-Studies range from 1966 to 2001
-Range in size of differ ent studies is huge
826 Ğ 899,750
-In general smaller studies give higher prevalence
-Total n umber of chil dren surveyed is around 5 milli on
Epidemiology of autism
Rates of autism
-Prevalence estimates range from 0.7/10,000 to 72.6/10,000
-Prevalence rates higher with smaller sample size
-average prevale nce 10/10,000
Mental retardation
-Assessment of intelle ctual fu nction in 20/32 studie s
-30% showed no intellectual impair ment (6.6-100%)
Gender
-male/female sex ratio averaged 4.3 over all studies
-Range 1.33 to 16
-No study ever id entifi ed more girl s than boys
-Gender diff erence greater in non-mentally retarded subjects
5.75 to 1 in normal intellectual function group
2:1 in groups with mental retardation
Neuropathology
Increased head size
-Kanner described large heads in some c hildren with autism
-Macrocephaly found in 20% of autistic in divid uals
-Not present in the fir st year of life
-Consistent with fin din g of increased brain weig ht
-Recent studies suggest that increases are transient (2-4 yrs)
-Neuroim agin g has shown in creased brain volume
Figure 1. Orthogonal views for segmenting the amygdala and hippocampus on MRI
sections
Schumann, C. M. et al. J. Neurosci. 2004;24:6392-6401
Copyright ©2004 Society for Neuroscience
Figure 5. Absolute left (a) and right (b) hippocampal volume (in cubic centimeters) by
diagnostic group for subjects 7.5-18.5 years of age (*p
Schumann, C. M. et al. J. Neurosci. 2004;24:6392-6401
Copyright ©2004 Society for Neuroscience
Neuropathology
What developmental processes might lead to a larger brain?
-Increased neurogenesis
-Increased gliogenesis, myelination
-Increased synaptogenesis
-Disturbed migration
-Decreased apoptosis
-Decreased dendritic pruning
Cellular pathology
Whole brain serial sections (Kemper and Bauman)
Six autistic cases and six age and sex m atched controls
Hip pocampus and amygdala
-Increased cell packing
-Reduced cell size
-Limited dendritic ar bors
Suggest
-Similar to earli er stages of brain development
-May refle ct features of an immature brain
Other brain regions
Cerebellum
-Decreased Purkinje cell number (Kemper and Bauman)
-Decreased Purkinje cell size (Fatemi)
-Decreased neuron size in deep cerebellar n uclei in ol der, but not young
autistic s ubjects
Cerebral cortex
-Course, poorly laminated cingulate cortex in 5/6 subjects (Bauman)
-No diff erence in neuron counts in frontal cortex (Bailey)
But other alteratio ns w ere visible
-thickened cortices
-high neuronal densitie s
-irr egular laminar patterns
-poor gray-white matter boundrie s
-Changes in laminar patterns c ould suggest defects in mi gratio n
Neuropathology summary
-Increased in head size
-Increased brain volume
-Increased volume of specifi c brain regions (hippocampus)
-Increased packing densities in some regio ns
-Decreased dendritic c omplexity
-Decreased cell neuron numbers in cerebellum
-Altered laminar patterns in cortex
-Possible changes in whit e ma tter or myelinatio n
Conclusion: Wide-ranging change that can be pretty subt le
Neurotransmitters
Alterations in many neurotransmitter systems in autism
-Glutamate
-GABA
-Serotonin
-Catecholamines (norepinephrine, dopamine)
-Neuropeptides
Changes in glutamate and/or GABA could lead to
alterations in excitation/inhibition
GABA- major inhibit ory neurotransmitter
-GAD (glutamic acid decarboxylase) is the rate-limiti ng enzyme in
GABA biosynthesis
-Westerns on postmortem brain tissue (n=4-8 control; n=5 autism)
48 and 50% decrease in 65kDa, parietal lobe and cerebellu m
61 and 51% decrease in GAD67 (Fatemi 2 002)
-Possible deletions in genes encoding GABA receptors
-Fewer GABA binding sites in hippocampus (Blatt 2001)
Serotonin
-Released by some populatio ns o f midbrain neurons
Project widely to other brain regions
-Involv ed in the regulation many processes
Sleep, mood, body temperature, appetit e
-Also im plicated in ea rly CNS development
Cell proliferation
Migration
Diff erentiation of neural progenitors
-Genetic changes in serotonin transporters and biosynthetic
enzymes have been sh own (Nabi 2004)
-Increased serotonin in the blood pla telets in autism (1961)
-Altered brain synthesis of serotonin (Chugani 1997)
Serotonin- Developmental changes
Cortical decreases of AMT uptake (red areas) I
n three autistic children in (1B) the frontal cortex
(left hemisphere), (1C) frontal and temporal cortices
(left hemisphere), and (1D) frontal, parietal and
temporal cortices (right hemisphere) are shown.
Is autism a genetic disorder?
Biological basis first suggested by Kanner (inborn
defect)
But a genetic basis wasnÕt widely believed
-WasnÕt hought
t
to run in families
-Few autistic children had autistic siblings (2%)
-No identified chromosomal abnormaliti es
-Autistic kids didnÕt have autistic parents
Is autism a genetic disorder?
BUTÉ .
At the time studies were done cytogenetic techniques
were pretty crude
Autistic people didnÕt tend to have children
2% rate of autism in siblings is about 50X normal
Family history of delayed speech
First autism twin study-1977
Folstein and Rutter, Nature 1977
-21 pairs of same-sex twins, one of with autism
-Twins classed at monozygotic (MZ) or dizygotic (DZ)
-11 MZ, 10 DZ pairs
-Twins and families were interviewed and tested
-Cases blinded for review and diagnosis
- Total 25 autistic individuals
-4/11 MZ pairs concordant for autism (36%)
-0/10 DZ pairs were autistic (0%)
Twin studies - Is autism a spectrum?
Do non-autistic MZ twins show other abnormalities?
Definition of cognitive disorder
-no phrase speech until 3 years old
-IQ 70 or below
-severely abnormal articulation after 5 years
-scholastic difficulties requiring special schooling
5/11 MZ non-autistic co-twins showed a cognitive
disorder (82% including autism)
1/10 DZ non-autistic co-twins showed such disorders
Further twin studies
Steffenburg 1989, Bailey 1995
-Swedish (1989) study showed 91% concordance for MZ, 0%
for DZ (11 pairs MZ, 10 DZ)
-Brit ish (1995) study showed 60% concordance for MZ, 5% for
DZ (25 MZ, 20 DZ)
-Extension to broader phenotype confir med
Social or cogniti ve problem in 90% of MZ non-autistic
twins
Only 10% of DZ non-autistic twins
-Enormous c lin ical variatio n even w hen concordant pairs had
the same genes
-More perinatal stress in autistic twin of discordant pairs
Conclusions from twin studies
-MZ and DZ comparison showed genetic contribution to
autism
-Broad phenotype of autism- spectrum disorder
-Likely to be environmental influence as well
-Difference between MZ vs DZ sibs suggests multiple
genes
Family studies also suggest genetic link
Pragmatic language problems (Landa 1992)
-Measured socia l language us e in parents and controls
-Autis m pa rents showed more atypical pragmatic behaviors
Disin hibited Social Communicatio n
Awkward/Inadequate Expression
Odd Verbal Interaction
-Milder, but sim ila r to social language deficits in autism
Unusual personality traits (Piven 1994)
-Autis m parents sig. hi gher on three measures
Alo of
Untactful
Undemonstrative
Social abnormaliti es (Priven 1990)
-Family histories of 67 adult sibs of 37 autistic probands
-Found a high fr equency of neuropsychiatric disorders
3% autistic
4.4% severe social dysfunctio n and isola tio n
15% cogniti ve disorders
15% affective disorder
Family studies-negative results
Negative fin din g in studies of cogniti ve patterns and depressio n
-No in creased lo adin g of lo w IQ in rel atives
-Language im pairm ents are not increased in relativ es
Intellig ence tests show hig her IQ in fir st degree rela tiv es
(Fombone 1997)
-Discrepancies in favor of verbal scores
-No diff erence on reading, spelli ng, performance scales
Looking for autism genes
Autism - an attractive disorder for gene hunting?
-Strong genetic component
-Reasonably small number of susceptibili ty genes (?)
-Standard diagnostic m easures
-MR and epilepsy c an be excluded from study populations
Disadvantages
-Lack of good candid ate genes
-Maybe too many genes (?)
-Uncertain ty about boundaries of phenotype
Three approaches for identif ying chromosomal loci
-Cytogenetic studies-chromosomal abnormalities
-Whole ge nome screens-lin kage between autism and genetic
markers in multi plex famili es
-Candid ate gene a naly sis-genes in linked loci that affect brain
development
Chromosomal abnormalities
-Several chromosomal abnormalit ies associated with autism
-Fewer than 10% of cases lin ked to chromosomal abnormalit y
-Often these are associated with individuals with autism
-The most fr equent seen region is 15q11-q13 (lo ng arm), 1-4% of
cases
-Duplicatio ns, deletions and inversions are seen
-Overlaps Prader-Willi/ Angelman criti cal region
Genes identified from linkage analysis
FOXP2
-Linked to a severe mo nogenic form of language impair ment
-Additi onal studies do not support a role as a susceptibilit y gene in
autism
RELN (reelin)
-Reelin regulates neuronal migr ation in cortex and cerebellu m
-Reeler mi ce have defects in a ggressio n, gait, novel object
detection
-Blood reelin le vels lo wer in autism famili es
-Postmortem autistic cerebellum showed 40% decrease in reelin
protein
-Additi onal studies didnÕtconfir m linkage
Genes identified from linkage analysis
Candidate genes at 15q11-q13
-GABA A receptor cluster
Contains 3 genes, GABRB 3, GABRA5 , GABRG 3
Mice deficient in B3 have epilepsy and learning and memory
deficits
Sequencing of GABAR s hows functional mutations in autism
-Not all individuals with 15q11-13 defects have autism
-Genes are not suffi cient for autism
Genes identified from linkage analysis
Neuroligin
-Cell adhesio n molecules important in synapse formatio n
-NLGN3 and NLGN4 mutations identifie d as mutated in screen of
158 autism mult iplex familie s (France)
-Overexpression of normal protein increases synapse formation,
overexpressio n of mutant protein leads to decreased synapse
formation
-These mutations are not present in Toronto or Quebec populations
-Neurolig ins may be responsible for a subpopulation of autism
Gene summary
-Several genes have been identif ied through linkage analysis and
candidate gene approaches
-No single key gene ha s been identifie d
-Current research hope to link in div idual genes to specifi c
behavioral abnormaliti es
-It will be necessary to understand interactions between multiple
genes
Controversies in autism
Causes of autism
-Incidence
-The role of the parent
-Vaccines
-Envir onmental toxins
-Food allergies
Treatments for autism
-Secretin
-Diets
-Facilit ated communication
-Drugs
-Behavioral
Behavioral/Social issues
-What distinguishes autism from other PDDs
-Male/female diff erences
-Mental retardation