Autism

Question 1

Pervasive developmental disorder (PDD)

Answer 1

Normal until interaction with environment
Delays in childhood development (eg autism) that are associated with atypical behaviours

Question 2

Autism and rates disorders (history)

Answer 2

1943 - identification of children that showed atypical behaviours
Sounded verbal skills
Social interaction
Repetitive behaviours

Otherwise normal development until social skills and skills needing the brain

Question 3

Autistic triad and a spectrum of disorders

Answer 3

Asperger’s - impaired social interaction, impaired restricted activity particularly focussed to inanimate objects

Autism - impaired social interactions, impaired restricted activity g focusing to inanimate objects and verbal communication or reduced language skills

Question 4

Appears in development and sustained

Answer 4

Developmental can mature over time - diagnosis of autism may be better defined by other syndromes
Cognitive dysfunction- high functioning/low functioning confuse diagnostics
Major cognitive syndrome present with behaviours that appear autistic but major dysfunction is mental retardation Retts and fragile X not autism
Retts and fragile x - defective gene identified so used as model

Question 5

Autism

Answer 5

Triad of dysfunction in social, communicative, repetitive behaviours
Range: 10/10000
Monozygotic twins and significant siblings = genetic component, clear complex polygenetic underpinnings, environmental interactions

Question 6

Asperger’s

Answer 6

Autistic disorder without dysfunctional verbal communication
1-60/10000
Genetic and environmental
Genes not clear

Question 7

PDD-NOS

Answer 7

Low level autistic spectrum, more common better prognosis
1/200
Less studied - environmental and environmental

Question 8

Hellers childhood disintegration disorder

Answer 8

Normal development followed by dysfunction in many areas beyond autism. Social skills less disrupted but severe decline in language skills
1/100000
Unclear but neuropathology implicated

Question 9

Fragile X syndrome

Answer 9

Mental retardation, modest autistic phenotype
1/5000
Males > females
Fragile x gene
RNA binding protein mutated

Question 10

Retts syndrome

Answer 10

Similar early symptoms, progresses to mental retardation
1/12500
MECP nuclear methyl DNA binding protein

Question 11

Diagnosis of autism

A. Persistent deficits in social communication and social interaction across contexts, not accounted for general developmental delays, manifests by 3 of 3 symptoms

Answer 11

1. deficits in social emotional reciprocity
2. Deficits in nonverbal communication behaviours
3. Deficits in developing and maintaining relationships

Question 12

Diagnosis of autism

B. Restricted, repetitive patterns of behaviour, interests or activities as manifested >2 of 4 symptoms

Answer 12

1. Stereotyped or repetitive speech, motor movements, use of objects
2. Excessive adherence to routines, ritualised patterns of verbal or non verbal behaviour or excessive resistance to change
3. Highly restricted, fixated interests that are abnormal in intensity and focus
4. Hyper or hypo reactivity to sensory input or unusual interest in sensory aspects of environment

Question 13

Diagnosis of autism

C. Symptoms must be present in early childhood but may not become fully manifest until social demands exceed limited capacities

Answer 13

Pervasive developmental disorder
Adult diagnosis too

Question 14

Ute firsth: sally anne test and theory of the mind

Answer 14

A test to recognise empathy and associated social skill in the young

2 dolls sally and Anne
Sally has a basket, Anne has a box
Sally has a marble puts it in her basket
Sally goes for a walk
Anne takes the marble and puts it in her box
Sally comes back, wants to play with her marble where will sally look for her marble?

Autistic child - will look in the box, told the story so knows where it is. Can’t put themselves in the position of sally who would be unaware it was taken

Normal child - will look in basket, can put themselves outside of themselves

Empathetic, feeling outside yourself

Question 15

Reality is that most with ASD diagnosis are not high performing

Answer 15

Sheldon - Big Bang theory probably Asperger’s
Non verbal, intense focus, hyper-hypo sensitivity, weird positioning system

Question 16

When does neurotypical becomes neuroatypical

Answer 16

More prevalent or diagnosed in males
Human females empathise: do well in behavioural scores of ability to predict and respond appropriately to others mental state (verbal fluency)
Human males systemise: predict and respond to behaviour of nonagentive deterministic systems by predicting rules that govern the system (map reading)

Quantitative tests - series of questions, score if individual empathiser or systemiser

Extreme male brain (autistic) = focused go against empathising nerve activity

Question 17

Change in diognosis

Answer 17

More balanced view of male and females
Females more likely to be empathisers , autistic = non empathetic so might miss diagnosis without the balance

Question 18

Does the triad represent a unique spectrum or overlap of traits?
Social, verbal and motor (repetitive) behaviours

Answer 18

Fractionable in normal population but some linkage between some but not significant
Poor expression of traits in the triad of autism- not completely fractionated as some socially biased test tease out association

Genetic inheritance of individual traits in triad (twin studies) argues for fractionation of traits

Question 19

Social brain areas

Answer 19

Cortical regions:
medial frontal cortex, temporparieatal junction, temporal suculus and poles

Question 20

Verbal brain areas

Answer 20

Voice centres of cortex

Question 21

Repetitive brain areas

Answer 21

Caudate putamen

Question 22

Biological basis of autism

Answer 22

Infer that underpinned by changes in brain structure and function
Electroencephalograms in autistics identify unusual patterns of electrical activity - reinforced by string association with seizures in autism (30%)
Changes in brain size relative to control pops (slow neonatal and rapid post natal growth)

Question 23

Imagining of abnormal development and connectivity of autism in post mortem brains

Answer 23

Cerebral cortex - cell number increased
Cerebellar cortex - cell number decrease
Deep cerevellar nuclei - size change
Inferior oil art nucleus - cell densit

Question 24

Normal brain development

Answer 24

Progenitor
Neurogenesis (proliferation)
Migration
Neural differentiation
Neurone outgrowth
Synapse formation
(Retraction and shrinkage during synapse formation)
Maturation and stabilisation
(Pruning synaptic sculpturing so retraction and shrinkage)

Done by 6/7 yrs old but connectivity continues
Matched with cell death to keep numbers of neurones as required

Question 25

Genetic basis providing insight to a synaptic locus for autism

Answer 25

Monozygotic twins have 90% coincidence of autism Siblings association too - polygenetic jn nature or complex regulation of de novo mutations Mutations can be followed by tracking in heritability of genes Chromosomal rearrangements cutoarchitecture identified and mutant associated with rearrangement Linkage or association using markers in genome to track regions of genome associated with grainy and infer molecular associated with this

Question 26

Genome wise association studies (GWAS) using genomic variation to map disease associated alleles

Answer 26

Powerful in autism not powerful in depression Patients DNA vs non patients DNA SINGLE NUCLEOTIDE POLYMORPHISMS Track single nucleotide polymorphisms Compare position and abundance Map of where they are associated with atypical Weight of genetic contribution of that gene

Question 27

Genetic architecture of autism

Answer 27

Strong genetic association Genetic variation Rare, highly penetrant variations 1 allele involved to > 1000 in low penetrant variations present at high frequency Complexity and spectrum >1000 genes implicated so far

Question 28

Many genes but good rationale to describe synaptopathy

Answer 28

Support a neurobiological and particularly synaptic basis for pathophysiology- often involved in nervous system (neurones) Synapse

Question 29

FMRP

Answer 29

Control transcription and express of genes involved in formation and stabilisation of synapses

Question 30

NLGN4 & 3

Answer 30

Cell - cell and synaptic contacts

Question 31

Other mutations

Answer 31

Regulate cytoskeleton and form and function of dendrites Protein organisation of synapse Directly control chemical transmission and excitibility Cell signalling (synapse function) Developmental processes that lead to synapse formation Control transcription and express of genes involved in formation and stabilisation of synapses Cell - cell and synaptic contacts

Question 32

Structure and function of Neuroligin

Answer 32

Post synaptic molecule in cell cell adhesion with presynaptic neurone Sits in membrane, faces synaptic cleft, associated in transymnatic fashion with neurexins (presynaptic) Removal of these expect synapse will fall apart Neurologin 1-4 Neurolexin 1-4 Neurexins thousands due to splicing

Question 33

Neurologin deficiency in animal models does not give expected effect but has autistic phenotype

Answer 33

Mice lacking neuroligin have brain, synapses and expected number of synapses (hippocampus/cortex) Die due to brain stem disrupted neural activity when all neuroligin removed (balanced +ve & -ve neural circuit) Brainstem normal number of synapses but glutamate and GABA transmitters reduced (fucundenty) Normal- inhibitory dominates in respiratory system Neuroligin deficient - excitatory dominates Synaptic dysfunction without loss of cells or synapses appears possibility (synaptic maturation?) Neurexin key susceptible gene EEG disrupted, imbalance characteristic

Question 34

Clarity and complication in human and animal models of autism

Answer 34

Neuroligin - expressed broadly but can have selective effect Mutated - neuroligin-3 in humans (R451C) Arginine to cysteine Neuroligin 3 mutation = increase inhibitory synaptic transmission Knock in mice showed no effect on social interaction 2 brothers: severe ASD symptoms including seizures early diagnosis, ASP with DSM diagnosis but milder diagnosis later

Question 35

Neuroligins mouse models of human condition

Answer 35

Neuroligin 3 mutated - protein made but not trafficked to cell surface so post synaptic neurone that lacks the neuroligin important in the signalling (10% gets to surface) INCREASED INHIBITION, IMPAIRED SOCIAL BEHAVIOUR, MODIFIED (IMPROVED) LEARNING Neuroligin 3 knock out - similar in outcome but phenotypivally distinct INCREASED METABOTROPIC GLUTAMATE RECEPTOR, DISRUPTED PLASTICITY IN CEREBELLUM

Question 36

Animal studies of genetic lesion to define key circuits underpinning fractionable pathophysiology of autism circuits

Answer 36

NLG-3 knock out and functional null NLG3R451C do not directly overlap Motor learning indicate shared ability for hyper function in motor control No difference in performance, learning process - stays on for longer each time X2 mutants falling off quicker than wild type- can’t compensate, dysfunction arises Disruption in motor control and learning Motor control: cerebellum, motor cortex, striatum (dorsal striatum) Selective rescue gene - none of the regions rescued the motor phenotype But ventral striatum (nuclear accumbens projects to VTA)

Question 37

Neuroligin 3 loss of function (KO & mutant) reduced inhibitory signals from GABA releasing onto D1 but not D2 neurones without effecting excitation

Answer 37

NL3 loss of function excitation to D1 and D2 pathways No change in excitation in D1 or D2 pathway Reduction in inhibition to D1, D2 still normally inhibited Less variable, increased performance based on repeat behavioural sequence Mutation profound enough to change behavioural response - repetitive behaviours - autism associated

Question 38

Therapy/treatment in autism

Answer 38

No cure Behavioural therapies to induce behavioural plasticity 1.sensory or play therapies to bring individual out of oneself 2. Encourage interaction with environment and others 3. Cognitive therapy: identify deficiencies, awareness and teach strategies to overcome these Drug therapies 1. Target neuro chemistry that underpin autistic triad (serotenergic and dopaminergic drugs eg haloperidol and resperidone) for social impairment and stereotypic behaviour, SSRIS for repetitive behaviours 2. Transmitter pathways that underline behavioural disorders associated with autism eg sleep disorders and aggression - propranolol or clonidine (adregergic antagonist)

Question 39

Issues with treatments

Answer 39

Evidence for efficacy tends to be clinical/anecdotal Few full trials on efficacy of drug or behavioural treatments