"Current Scientists Perspectives of Autism Medical Genetics Children s Hospital of Pittsburgh June 3, 2008 Nancy Minshew, MD Director, NIH Autism Center of Excellence University of Pittsburgh
Key Features of Autism 1. Impaired social reciprocity 2. Impaired social communication 3. Repetitive, stereotyped interests & behavior 4. Onset in first 2-3 years of life Q: Is the constellation inherent in a cohesive syndrome or is it an artifact of diagnostic practice? Courtesy of Michael Rutter Autism: Clinical features and research challenges
Some Key Clinical Features of Autism 1. Marked male preponderance (3-4:1) BUT this applies to most neurodevelopmental disorders 2. Association with intellectual impairment BUT IQ range extends from severely impaired to superior 3. Association with epilepsy in 25-33% with onset in adolescence 4. Association with increased head circumference Courtesy of Michael Rutter Autism: Clinical features and research challenges
Some The Biological Top 10 of Features 2007 (cont d.) of Autism 1. Raised serum serotonin in 30% but nonspecific 1. 2. Spontaneous No consistent Mutations: or marked Increased response rate to of psychotropics de novo copy number variations: submicroscopic deletions or 3. duplications Very limited of generalization DNA sequences. of More responses common to in psychological interventions simplex than multiplex families. Opened door to two 4. genetic Brain imaging: mechanisms: no localized inherited abnormality, gene mutations rather and an spontaneous impaired integration copy number across mutations- systemsinstability in 5. replication No consistent of DNA neuropathological pattern except 2. Potential findings reversal suggest of prenatal Neurodevelopmental origin Disorders (in Fragile X, Rett & Angelman Syndromes) in adult mice Courtesy of Michael Rutter Autism: Clinical features and research challenges
The Medical Top 10 of Associations 2007 (cont d.) 1. Association with some diagnosable medical 1. Spontaneous condition in Mutations: least 10% Increased of cases rate of de novo copy number variations: submicroscopic deletions or 2. Strongest association with tuberous sclerosis but duplications of DNA sequences. More common in simplex largely than a function multiplex of families. location Opened of tubers, door low to two IQ genetic and epilepsy mechanisms: inherited gene mutations and 3. spontaneous Definite, but copy weak number association mutations- with instability fragile in X replication anomaly of DNA 2. Potential reversal of Neurodevelopmental Disorders (in Fragile X, Rett & Angelman Syndromes) in adult mice Courtesy of Michael Rutter Autism: Clinical features and research challenges
Some The Genetic Top 10 of & Related 2007 (cont d.) Features 1. Marked increase in familial risk (50x) 1. Spontaneous Mutations: Increased rate of de novo copy 2. Heritability circa 90%, 3-12 genes involved number variations: submicroscopic deletions or 3. duplications Increased rate of DNA of chromosomal sequences. More anomalies common in (but simplex diagnostically than multiplex nonspecific) families. Opened door to two 4. genetic Increased mechanisms: rate of congenital inherited gene anomalies mutations but and apart spontaneous from ch 15, copy nonspecific number mutations- instability in replication of DNA 5. Association with increased parental age 2. Potential reversal of Neurodevelopmental Disorders (in 6. Fragile Increase X, in Rett copy & Angelman number Syndromes) variations in adult mice Courtesy of Michael Rutter Autism: Clinical features and research challenges
Courtesy of: http://www.autismspeaks.org/science/science_news/top_ten_autism_research_events_2007_main.php
The Top 10 of 2007 1. Spontaneous Mutations: Increased rate of de novo copy number variations: submicroscopic deletions or duplications of DNA sequences. More common in simplex than multiplex families. Opened door to two genetic mechanisms: inherited gene mutations and spontaneous copy number mutations- instability in replication of DNA
The Top 10 of 2007 1. Potential reversal of Neurodevelopmental Disorders (in Fragile X, Rett & Angelman Syndromes) in adult mice
The Top 10 of 2007 (cont d.) (cont d) 1. 3. Spontaneous Autism Genome Mutations: Project (AGP): Increased largest rate of genetics de novo copy number consortium, variations: launched submicroscopic in 2004, largest deletions study ever or duplications conducted to of find DNA the sequences. genes associated More with common risk in of simplex developing than autism. multiplex 50 academic families. and Opened research door institutions to two genetic from 19 mechanisms: countries, pooled inherited resources gene mutations and used DNA and spontaneous microarray to copy scan number the human mutations- genome instability for genetic in causes replication of autism; first of DNA analyses made public in 2007. Nature 2. Potential Genetics 2007. reversal Chromo of Neurodevelopmental 2, 7, and 11 plus linkage Disorders signals (in Fragile only present X, Rett in girls, & Angelman identification Syndromes) of a specific in adult candidate mice gene neurexin, associated with copy number variation
The Top 10 of 2007 (cont d.) (cont d) 1. 4. Spontaneous First drug approved Mutations: by Increased FDA to rate treat of de symptoms novo copy number variations: submicroscopic deletions or associated w/ autism; Risperdal duplications of DNA sequences. More common in 5. simplex PTEN conditional than multiplex knock families. out Opened mice display door to two genetic enlarged mechanisms: brains and inherited social gene behavioral mutations deficits: and spontaneous PTEN interacts copy number with several mutations- proteins instability a in replication signaling of cascade DNA that are tied to tuberous 2. Potential sclerosis reversal and neurofibromatosis. Neurodevelopmental 17% Disorders of (in Fragile X, Rett & Angelman Syndromes) in adult mice individuals with autism & macrocephaly had PTEN gene. KO mice raises rescue possibilities.
The Top 10 of 2007 (cont d.) (cont d) 1. 6. Spontaneous Mouse models Mutations: of genes Increased associated rate of with de novo autism copy in number variations: submicroscopic deletions or humans: neuroligin-3 gene mouse model: mouse duplications of DNA sequences. More common in simplex has deficits than multiplex in social families. behaviors Opened and door an increased to two genetic ability mechanisms: for spatial learning inherited gene mutations and 7. spontaneous Functional copy connectivity: number mutations- neural deficits instability not in in a replication single structure of DNAbut in wiring that networks that 2. Potential connect reversal different of parts Neurodevelopmental of brain. Disorders (in Fragile X, Rett & Angelman Syndromes) in adult mice
The Top 10 of 2007 (cont d.) (cont d) 8. Discovery of rare families with SHANK3 gene 1. Spontaneous mutations added Mutations: further Increased evidence rate to of synaptic de novo copy number dysfunction variations: hypothesis. submicroscopic Codes for deletions synapse or formation duplications & maintenance. of DNA It also sequences. interacts More with common neuroligins in and simplex neurolexins. than multiplex families. Opened door to two 9. genetic Lack of mechanisms: response to inherited name at gene one year mutations is one and of spontaneous earliest signs copy of autism; number signs mutations- of autism instability can be in replication identified at of 14 DNA mos in half of cases 2. 10. Potential Parental reversal age (paternal of Neurodevelopmental or maternal or both) Disorders related (in Fragile to but not X, Rett necessarily & Angelman the cause Syndromes) of increased in adult risk mice of autism.
The Transforming Top 10 of 2007 Findings (cont d.) 1. Autism as a disorder of complex information 1. Spontaneous processing Mutations: Increased rate of de novo copy number variations: submicroscopic deletions or 2. Autism as a disorder of connectivity duplications of DNA sequences. More common in 3. simplex Autism than as a multiplex disorder families. of dysregulated Opened door growth to two of genetic the cerebral mechanisms: hemispheres-gray inherited gene and mutations white and matter spontaneous but not cc copy number mutations- instability in 4. replication CNV in simplex; of DNA synapse-related genes in 2. Potential simplex reversal & multiplex of Neurodevelopmental families Disorders (in Fragile X, Rett & Angelman Syndromes) in adult mice
The Top Conclusions 10 of 2007 (cont d.) 1. HGF promotes a generalized increase in growth 1. Spontaneous and branching Mutations: in both Increased basal and rate apical of de dendrites novo copy number in layer variations: 2 pyramidal submicroscopic cortical neurons. deletions or duplications of DNA sequences. More common in 2. simplex Acts through than multiplex MET receptor families. Opened expressed door by to these two genetic neurons. mechanisms: inherited gene mutations and 3. spontaneous Both expressed copy number in cortical mutations- plate by instability E14: in replication -HGF layers of 4 DNA and 5 2. Potential reversal -MET layers of Neurodevelopmental 2, 3, 4, and 5 Disorders (in Fragile X, Rett & Angelman Syndromes) in adult mice
The Top Conclusions 10 of 2007 (cont d.) 1. Genes involved in autism vulnerability are likely 1. Spontaneous to be involved Mutations: in multiple Increased biologic rate of processes de novo copy both number within and variations: outside submicroscopic of the CNS. deletions or duplications of DNA sequences. More common in 2. simplex Neuropathologic than multiplex abnormalities families. Opened observed door to in two genetic autistic mechanisms: individuals inherited are consistent gene mutations with many and of spontaneous the processes copy involving number mutations- MET/HGF. instability in replication of DNA 2. Potential reversal of Neurodevelopmental Disorders (in Fragile X, Rett & Angelman Syndromes) in adult mice
Pathophysiologic sequence of a The Top 10 of 2007 (cont d.) neurodevelopmental disorder 1. Abnormalities Spontaneous Mutations: in Genetic Increased Code for rate Brain of Development de novo copy number variations: submicroscopic deletions or duplications Abnormal of Mechanisms DNA sequences. of Brain More Development common in simplex than multiplex families. Opened door to two genetic Structural mechanisms: and Functional inherited Abnormalities gene mutations of Brain and spontaneous copy number mutations- instability in replication Cognitive of DNA& Neurologic Abnormalities 2. Potential reversal of Neurodevelopmental Disorders (in Fragile X, Rett & Behavioral Angelman Syndromes) in adult mice
Official Category in DSM-IV: Pervasive Developmental Disorder Autistic Disorder Asperger s Disorder Pervasive Developmental Disorder Not Otherwise Specified Childhood Disintegrative Disorder (onset: 4-12 yr) Rett s Disorder
Informal Category Not in DSM-IV: Autism Spectrum Disorders Autistic Disorder Asperger s Disorder Pervasive Developmental Disorder Not Otherwise Specified Accurate distinctions between these outside a research setting unlikely. Need a functional definition in social, language, and adaptive abilities and problem behaviors instead.
Recognizing ASD in Able More Individuals Strange or odd: reflects social impairment Monotone voice: usually too loud Little to no facial expression Upset by change, rituals for doing things in set ways; scripts for saying things Obsessions- with collecting stuff or a topic; super memory for facts or attention to small details Clumsy, awkward
Recognizing ASD in Those More Affected Intermediate severity: echolalic, few scripted stereotyped sentences; socially isolated; selfstimulatory behavior; difficulty with change; sensory issues Most severe: no language, no comprehension, no prosody, no adaptive behavior- out of proportion to IQ; direct care staff can tell who has autism vs non-autistic MR- they are highly familiar with IQ expectations
Social Emotional Immaturity: Disturbance in Affective Contact Not Included in DSM Capacity to experience, comprehend, and regulate emotions at a basic and cognitive level is severely impaired and unrecognized, despite frequent abnormal imaging abnormalities of the amygdala, an emotion structure of the brain. Most verbal ASD adults are sociallyemotionally 12-18 months to 4-5 years of age. Failure to recognize this in treatment worsens behavior.
Common Principles of Neurology Brain disturbances produce a constellation of cognitive & neurologic deficits, not a single deficit Multi-organ involvement is the rule in nonacquired neurologic disorders- because affected genes are in every cell in the body
Neurologic Approach to Deciphering Disease Neurologists approach to investigating brain dysfunction is to characterize all impaired abilities AND all intact abilities to define common principles or characteristics of the underlying disease process.
Identifying the Cognitive & Neurologic Basis of Autism: Beginning with the Right Questions
The Profile of Intact & Impaired Abilities in High Functioning Autistic Individuals Intact or Enhanced Attention Sensory Perception Elementary Motor Simple Memory Formal Language Rule-learning Visuospatial processing Cognitive Weaknesses Complex Sensory Complex Motor Complex Memory Complex Language Concept-formation Face Recognition
What Does The Profile Mean About Neurologic Function & Neural Circuitry? Simpler processing & abilities are intact/enhanced Information processing capacity is limitedintegrative processing & higher order cognitive abilities are disproportionately impacted Inference: higher order circuitry is under developedthey are reliant on lower order circuitry & basic cognitive abilities to function.
fmri Activation During a Spatial Working Memory Task (Courtesy John Sweeney) Healthy Group Autism Group
Brain activation during sentence comprehension in autism In Brain, 2004 Autism group has less activation in Broca s area (a sentence integration area) than the control group and more in Wernicke s area (a word processing area) Results are consistent with poorer comprehension of complex sentences, coupled with good word reading (spelling bee champs)
Reliably lower functional connectivity for autism participants between pairs of key areas during sentence comprehension (red end of scale denotes lower connectivity)
Functional Connectivity The activation in two cortical areas can be less synchronized (upper panel) or more synchronized (lower panel) for different people
Reliable differences in functional connectivity: autism group has lower functional connectivity but same rank order
Functional Underconnectivity: fmri of the Tower of London Marcel Just Nancy Minshew Tim Keller Vlad Cherkassky Rajesh Kana Just et al., 2006 [Epub ahead of print], Cereb Cortex
How the mind organizes information, Or not in the case of autism Cognitively the problem is with prototype formation and automatic processes as opposed to conscious, verbally mediated reasoning.
Pitt Infant and Toddler Development Center Abilities that adults take for granted that normally develop in infancy and toddlerhood: For example: Our abilities to recognize faces and emotional expressions Our abilities to understand the difference between basic categories in the world cats, dogs, lions
Infants are born with automatic mechanisms that allow them to form Prototypical Representations of Information
Which of these is the best example of a dog?
Which of the following two faces looks more familiar to you?
1 2
Gender Categorization 5- to 7- Year- Old Children 100 95 90 85 80 75 70 65 60 55 50 * * Typical Hair Typical Cap Atypical Hair Atypical Cap Strauss, M.S. et al., Child Development (under revision) *p <.05 Control Autism
Gender Categorization 13- to 17- Year Old Teenagers 100 95 90 85 80 75 70 65 60 55 50 Typical Hair Typical Cap Atypical Hair Atypical Cap * * Control Autism *p <.05
TYPICAL SOMEWHAT TYPICAL ATYPICAL
R 0.30% 0.25% 0.20% Biological Non-biological psts Region psts Region 0.15% 0.10% 0.05% Robot Clock Mechanical Human Human 0.00% Autism Neurotypical What are the brain systems involved in representing the actions and intentions of other people? t > 5.2, p <.001 R 1.00% 0.80% 0.60% 0.40% 0.20% 0.00% MT/V5 MT/V5 Autism Biological Non-biological Neurotypical Pelphrey et al. (2003) Journal of Neuroscience Carter & Pelphrey (2007) Social Neuroscience
A % Signal Change % Signal Change Typically Developing - Right Superior Temporal Sulcus 0.40% 0.30% 0.20% 0.10% 0.00% Congruent Incongruent -3 0 3 6 9 12 15 Time (in seconds) -0.10% Congruent Neurotypical Incongruent Autism B % Signal Change -0.20% 0.40% 0.30% 0.20% 0.10% 0.00% -3 0 3 6 9 12 15 Time (in seconds) Autism - Right Superior Temporal Sulcus Congruent Incongruent -0.10% -0.20% -3 0 3 6 9 12 15 Time (in seconds) 0.12 All Eye Movements 0.08 R 2 = 0.7683 0.04 0.00-0.04 R -0.08 Incongruent > Congruent 0 10 20 30 40 Pelphrey et al. (2005) Brain
Autism Typically Developing Pelphrey et al. (2002); Journal of Autism and Developmental Disorders