Neurobiology of Disease 7 Flashcards
How has the prevalence of autism changed since the early 1990’s? (1)
a) increased
b) stayed the same
c) decreased
a) increased
What is the estimated prevalence of autism in the USA (in children under 8 years)? (1)
a) 1 in 10,000
b) 1 in 68
c) 1 in 10
d) 1 in 5000
b) 1 in 68
Complete the sentence relating to the prevalence of autism. (3)
The prevalence of autism is thought to be …………………. higher in the ……………………. sex than in the …………………….. sex.
5-fold
male
female
For a diagnosis of autism to be made, three symptoms must be experienced in at least two core domains.
What are the core domains in which deficits are seen in ASD? (4)
- Atypical social behaviour
- Disrupted verbal and/or non-verbal communication
- Restrictive interests and/or repetitive behaviours
- Impairments in symbolic/imaginative play
For a diagnosis of ASD to be made, deficits/symptoms must have onset before what age? (1)
3 years
Give 7 specific signs of autism in young children. (7)
Give a criterion which these symptoms must meet to be classed as ‘autistic’. (1)
- Inability to relate/communicate with children or adults
- Poor speech or lack of speech
- Inappropriate laughter or crying
- Oversensitive or undersensitive to sound
- Inappropriate playing with toys
- Difficulty dealing with changes in routine
- Oversensitive or undersensitive to touch
CRITERION: must be developmentally inappropriate behaviour
Give 6 conditions/features which may be associated with autism but which are not core features/symptoms. (6)
- Heterogenous delay in spoken language
- Epilepsy
- Mental retardation
- Motor impairments
- Sleep disturbances
- Gastrointestinal disturbances
How common are speech delay and GI disturbances in autism? (1)
Feature in about 50% of people
How is head size thought to relate to autism? (1)
People with autism have been found to have ~20% larger head size
Describe how intelligence is thought to relate to autism. (3)
Most people have normal intelligence
35-50% have intellectual disability (IQ<70)
Small minority have remarkable memory/intellect
True or false? Explain your answer if appropriate. (1)
Autism is associated with mood and anxiety disorders, as well as ADHD.
True
Give three reasons/features of ASD which make a diagnosis difficult. (3)
- No common macroscopic or microscopic neuropathology
- No specific brain region or cell type is implicated
- No biomarkers, so no prediction of who will develop the condition
As well as psychiatric and psychological assessment, give two other tests which may be helpful in diagnosing autism. (2)
- eye tracking movements
- EEG
How can eye tracking movements be useful when diagnosing autism? (1)
Autistic people tend to make less eye contact
Autism spectrum disorder is a combined diagnosis, which used to be three separate diagnoses.
What are the three diagnoses which used to be used? (3)
- Autistic disorder
- Asperger’s disorder
- Pervasive developmental disorder - not otherwise specified (PDD-NOS)
Is autism usually treated using pharmacological or non-pharmacological management? (1)
Describe this management. (1)
Non-pharmacological management
Behavioural intervention
There are two FDA-approved drugs for treating autism.
What group do these two drugs belong to? (1)
Name the drugs. (2)
What are they for? (2)
Antipsychotics
Risperidone (for aggressive and repetitive behaviour)
Aripiprazole (for irritability)
What percentage of autism is inherited through a single mendelian gene mutation? (1)
3%
5% of autism cases are inherited through chromosome abnormalities and CNVs.
What is a CNV? (1)
Copy number variation - large sections of the genome are replicated or deleted
5-10% of autism cases are thought to be due to De novo single gene mutations.
What is a De novo single gene mutation? (1)
A mutation in a gene that is present in the offspring but not inherited from either parent (may occur after fertilisation).
What is the most common type (accounting for 80-85%) of autism genetics? (1)
a) De novo single gene mutations
b) Mendelian single gene
c) Chromosome abnormalities and CNVs
d) Unknown and/or multifactorial genes
d) unknown and/or multifactorial genes
What is the chance of a child with an autistic sibling developing autism? (1)
What does this suggest about the aetiology of autism? (1)
20%
Mix between genetic and environmental risk factors
Complete the sentence relating to autism. (2)
Autism is a disorder of …………………………, especially in the ………………………….
neuronal connectivity
cerebral cortex
Give two neuroanatomical differences which may be caused by genes implicated in autism. (2)
- Altered brain growth (smaller, then larger, then size becomes normal)
- Subtle differences in cerebral neuronal columns
Describe two systems-level differences which may be caused by genes implicated in autism. (2)
- Differences in prenatal neuronal migration and axon pathfinding, leading to differences in white matter tracts and functional connectivity
- Differences in postnatal dendritic development, synaptic pruning, and neurogenesis (balance of excitation/inhibition)
Describe three cellular/molecular differences which may be caused by genes implicated in autism. (3)
- Alterations in activity-dependent protein synthesis
- Differences in neuronal activity
- Differences in neuronal cell adhesion
Complete the sentence relating to the involvement of genetics in autism. (3)
In autism, >100 susceptibility genes converge on pathways affecting …………………….., ……………………….., and ……………………..
synapse formation
neuronal activity
neuronal cell adhesion
The gene alterations often seen in autism lead to changes in synaptic function and neuronal circuitry.
Give six specific cellular mechanisms/targets that the implicated genes may affect. (6)
- Synaptogenesis and synaptic plasticity
- Protein synthesis
- Chromatin remodelling and transcription
- Protein degradation
- Phospholipid homeostasis
- Cytoskeleton dynamics
Give five specific genes which are well-known to be involved in autism. (5)
- Neurexins
- Neuroligins
- DAT
- D2 receptor
- Trio gene
The trio gene is well-known to be involved in autism.
Are mutations in this gene generally inherited or de novo? (1)
Where is the protein formed from the trio gene found? (1)
de novo
Protein found in dendritic spines of glutamatergic neurones
Neuroligin genes are often implicated in autism.
Describe what the neuroligin protein is and its functions. (4)
Synaptic cell adhesion molecules
on postsynaptic neuronal membranes
which interact with glutamatergic NMDA or GABAergic receptors
to maintain synaptic functions and the excitatory/inhibitory balance
Neurexin genes are often implicated in autism.
Describe what the neurexin protein is and its functions. (2)
Components of the presynaptic neuronal membrane
intracellular domain interacts with proteins involved in exocytosis
Neurexin and neuroligin genes are implicated in autism.
Very briefly describe the joint function of neurexins and neuroligin proteins. (2)
Proteins form links across the synaptic cleft
and maintain synaptic function
Complete the sentence relating to genetics in autism. (2)
A small percentage of ASD patients present with single mutations in genes encoding the neuroligin-neurexin cell adhesion molecules, which modifies …………………………. and the …………………… balance.
Cell/synaptic adhesion
excitatory/inhibitory
R451C mice are also known as neuroligin-3 mutants. They show altered GABA signalling.
Give one functional, one histological, and one behavioural change seen in R451C mice. (3)
What neurological condition might this mouse model be used to replicate? (1)
- Increased IPSPs
- Increased number of GABAergic neurones (shown by increased VGAT)
- Reduced social interaction behaviour
May be used to replicate autism
Describe the differences which may be seen regarding D2 receptor expression in autism. (1)
How might this difference be imaged in human postmortem brain tissue? (1)
Increased D2 receptor expression in dorsal striatum
Immunohistochemistry or in situ hybridisation for D2 mRNA
Human dopamine transporter T356M has impaired function. It has been implicated in autism.
Describe the rate of uptake and the maximum uptake that would be expected with the T356M transporter compared to wild type. (2)
Slower rate of uptake
Lower maximum uptake
Human dopamine transporter T356M has impaired function. It has been implicated in autism.
Describe the exact mutation which takes place. (1)
Why is this mutation particularly devastating for the function of the protein? (1)
On which transmembrane domain of the DAT protein does the mutation have an effect? (1)
Threonine to methionine
The threonine residue is highly conserved across species, which suggests it must be important for protein function
Mutation affects transmembrane domain 7
Human dopamine transporter T356M has impaired function. It has been implicated in autism.
In Drosophila activity assays, what effect does this mutation, and also complete knockout of the protein have on activity? (2)
Describe the activity assay in Drosophila, and how activity would have been measured. (2)
Increased activity in both forms
Flies put in tube with infrared beam separating them from food
Measure how many times fly crosses beam to get to food
Suggest 2 mechanisms by which antipsychotics may work as an adjunctive therapy for MDD along with antidepressants. (2)
- Block D2 receptors to reduce dopaminergic neurotransmission
- Block other monoamine receptors (including 5HT receptors) to make the effects of antidepressant medication more specific
Describe an environmental risk factor for autism. (2)
Maternal/paternal age:
- In females, risk doubles from 25 to 40yrs
- Risk also increased if father is 10 or more years older than mother
Give eight possible neurobiological mechanisms which may lead to development of autism. (8)
- Mitochondrial dysfunction
- Chronic neuroinflammation
- Oxidative stress
- Dysregulation of monoaminergic neurotransmission
- Glutamate/GABAergic imbalance
- Hormonal imbalance
- Immune dysregulation
- Environmental toxins and stressors
Name two neurotransmitters which may be particularly affected in autism. (2)
- Dopamine
- Serotonin
Describe briefly how serotonin may be altered in autism. (1)
Could be increased or decreased
Elevated whole blood serotonin (hyperserotonaemia) is seen in about 25% of children with autism.
Apart from autism, give another neurological condition in which hyperserotonaemia is seen. (1)
Obsessive Compulsive Disorder
Elevated whole blood serotonin (hyperserotonaemia) is seen in about 25% of children with autism.
Suggest four mechanisms by which hyperserotonaemia may occur in autism. (4)
- Increased production by enterochromaffin cells in intestine
- Increased uptake of 5HT into platelets
- Decreased metabolic breakdown of 5HT
- Altered platelet release of 5HT
Describe the effects of tryptophan depletion on autistic symptoms. (2)
Worsened repetitive behaviour
Worsened irritability
Describe how 5HT2a receptor binding is altered in adults with Asperger’s syndrome and parents of children with autism in neuroimaging studies. (1)
Decreased 5HT2a receptor binding
Alterations in 5HT deactivation mechanisms have been associated with ASD.
Give two genes/proteins which may be altered. (2)
SERT
MAO-A
Complete the sentence relating to SERT and autism. (3)
Genetic knockout of SERT alters overall ……………………., including growth, and interneuron migration to the …………………….
These changes may be related to ……………………..
brain development
cortex
autism
True or false? Explain your answer if appropriate. (1)
Due to the altered serotonergic function in autism, SSRIs often are of therapeutic benefit and are commonly prescribed
False - SSRIs have little therapeutic benefit in ASD
Describe how the short allele for the promotor region for the SLC6A4 genes may lead to a specific autistic phenotype. (3)
Short allele leads to less transcription of SERT
So reduced SERT function
Which is associated with anxiety-related traits and altered brain structure