Week 5

Question 1

By studying gene-behaviour relationships in neurodevelopment disorders that have a strong genetic origin we can:

Answer 1

Improve diagnostic reliability
Reduce time to diagnosis
Tease apart the causes of problem behaviours
Develop sensitive and appropriate treatment options

Question 2

neurodevelopmental disorders

Answer 2

Result of impairments to typical growth or development of the brain and nervous system
Can result from intrauterine environment (hormone imbalance, intrauterine infection, alcohol, tobacco or drugs during pregnancy), extrauterine environment (preterm birth, brain injury, heavy metal exposure) or genetics (chromosomal disorders, single gene disorders or multiple gene disorders)

Question 3

single gene disorder examples

Answer 3

fragile x, Williams syndrome

Question 4

polygenic disorder examples

Answer 4

ASD, ADHD

Question 5

genes

Answer 5

distinct sequence of DNA forming part of a chromosome, which is the blueprint for a protein
Genes orchestrate generating new brain cells, getting them to migrate to the right spots, forming connections between those neutrons and pruning back unnecessary connections
Once the brain is fully formed, genes responsible for producing proteins in the brain and maintaining health of the cells in the brain

Question 6

alleles

Answer 6

variants of a gene

Question 7

SNP

Answer 7

variation in a single nucleotide that occurs at a specific point in the genome

Question 8

fragile x

Answer 8

Intellectual disability, behavioural and learning challenges and specific physical characteristics (large ears, elongated face, hyperextensible joints, low muscle tone)
Over half also meet criteria for autism 
More males (only have on x chromosome)
Caused by the expansion or lengthening of the FMR1 gene on the x chromosome, switches off production of protein FMRP, which is involved in brain development and other functions 
FMRP essential for normal cognitive development, female reproductive function, and also expressed in neurons for synaptic plasticity

Question 9

fragile x treatment

Answer 9

Work with clinicians to assist in:
Language and communication (speech pathology, OT)
Managing anxiety
Physiotherapist to improve muscle tone
Special educator to improve learning settings
Psychologists to work with whole family

Question 10

polygenetic disorders

Answer 10

Diagnosed by clinicians according to behavioural presentation
Arise from a constellation of multiple SNPs across multiple genes, which gives rise to the diversity of clinical presentation
Highly heritable

Question 11

heritability

Answer 11

Amount of variation in a phenotypic trait in a population that can be attributed to genetic variation among the members of that population

Question 12

phenotypic trait

Answer 12

obvious and observable trait

Question 13

genetic variation

Answer 13

number of different alleles of genes in a population
Variation of a behavioural trait that is attributed to genetic variation: what proportion of a trait can be attributed to different gene variants in a population

Question 14

how do we estimate heritability

Answer 14

Parents to offspring
Comparing siblings
Comparing twins (identical and non identical)

Question 15

broader autism phenotype

Answer 15

Broad autism phenotype is a term used to describe non-autistic relatives who display sub threshold autistic symptoms (parents, siblings)
Demonstrative of genetic basis of autism

Question 16

ADHD

Answer 16

Most heritable neurodevelopment disorder (0.70-0.87 heritability)
Persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequently displayed and more severe than is typically observed in individuals at a comparable level of development

Question 17

diagnosing ADHD

Answer 17

No single test, usually several rating scales used to track symptoms in a variety of settings
Symptoms must be exhibited prior to 7 years of age, and be present for >6 months

Question 18

ADHD symptoms divided into

Answer 18

inattention

hyperactivity/impulsivity

Question 19

ADHD treatment

Answer 19

Main treatment is stimulant medication: methylphenidate and dexamphetamine
Non stimulants such as atomoxetine also used
Stimulants effect size is greater than non stimulants

Question 20

methylphenidate ADHD

Answer 20

increases dopamine levels in brain; increases availability of dopamine at the synapse; dopamine helps signalling between neurons by attaching to dopamine cell receptors
This tells us that there is likely something wrong with the genes that code for parts of the dopamine system in ADHD (dopamine neurotransmitter, transporter or receptor)

Question 21

candidate gene

Answer 21

A gene that is thought to be involved in a trait or disorder
Normally chosen based upon prior physiological, genetic or biochemical characterisation that leads one to suspect that this gene is involved in the trait

Question 22

DAT1

Answer 22

one allele of this gene is associated with excessive reuptake of dopamine, leading to under activity in dopamine pathways

Question 23

DRD4

Answer 23

one allele is associated with a sub sensitive post synaptic receptor (not as sensitive to dopamine)

Question 24

Associations between DAT1 and attention

Answer 24

ADHD have difficulty with sustained attention and more frequently, momentary lapses in attention
Children with ADHD groups as either carrying ‘high risk’ or ‘low risk’ DAT1 allele
High risk DAT1 group displayed greater response variability on the SART than either the low risk or healthy controls, whereas the latter two did not differ

Question 25

ASD

Answer 25

Highly heritable Classified according to DSM-5 criteria: core deficits in 1. Social communication/interaction and 2. Restricted and repetitive behaviours

Question 26

behaviour ASD

Answer 26

poor sensory integration, ‘local information bias’

Question 27

neuropathology ASD

Answer 27

cortical minicolumns, reduced connectivity between cortical areas

Question 28

candidate genes ASD

Answer 28

CNTNAP2, SHANK3, neurexin, reelin

Question 29

classic symptoms ASD

Answer 29

Classic symptoms include delayed language development, motor problems and gaze avoidance Abnormalities in cerebellar vermis: either too small (B: hypoplasia) or too large (D; hyperplasia) relative to controls (C) Language delay, motor problems and gaze avoidance are also common to children who have cerebellar lesions or surgical removal of the cerebellar vermis

Question 30

EN2 and formation of the human cerebellum

Answer 30

Homeobox genes orchestrate the formation of many body structures during early embryonic development EN-2 is an autism candidate gene EN-2 is responsible for regulating the timing of Purkinje cell maturation and perinatal cerebellar patterning Implicated in ASD from family linkage studies

Question 31

epigenetics

Answer 31

Study of how gene activity is regulated, and how genes are expressed, independent on an individual’s genetic sequence

Question 32

Gene-behaviour relationship in ASD

Answer 32

Children who have autism without a history of language delay (formerly Asperger’s disorder) show little or no cerebellar abnormalities Symptoms that are present in only a subset of individuals with ASD (e.g. language delay) therefore may represent a subtype of ASD, which has a distinct neurobiology and genetic aetiology to those without that symptoms May have ramifications for development trajectory, associated symptoms, treatment outcomes

Question 33

How we study behaviour-brain-gene relationships

Answer 33

studies comparing individuals, siblings, parents and families animal models gene and protein expression in humans (cadaver) or animal brain tissue cell culture (gene expression, study up/down regulation of protein expression)

Question 34

limitations of current approach to diagnosis

Answer 34

Relies on subjective interpretation of behavioural symptoms Overlap in current DSM-5 symptom descriptions for different disorders can make distinguishing disorders or determining co occurrence problematic Two different clinicians can yield different diagnoses Time to diagnosis can be long and drawn out Substantial heterogeneity within disorders, and the potential for shares pathophysiology between these disorders means it is difficult for clinicians to make predictions about course, outcomes, response to treatment and indeed what treatments should be offered.

Question 35

little success finding genetic causes for neurodevelopment disorders

Answer 35

Single symptom can arise from multiple causes Heterogeneity within disorders Overlap between disorders Classifying disorders as discrete categories doesn’t fit with biology Frustrating for individuals diagnosed, and their care givers, in selecting appropriate treatments, predicting course and outcomes of the disorder Problem is poor specificity of the disorders that we are attempting to map our findings back onto (heterogeneity)

Question 36

RDoC

Answer 36

New approach to classifying psychiatric disorders starting with the following assumptions: A diagnostic approach based on the biology as well as the symptoms must not be constrained by the current DSM categories Mental disorders are biological disorders involving brain circuits that implicate specific domains of cognition, emotion or behaviour Each level of analysis needs to be understood across a dimension of function Mapping the cognitive, circuit and genetic aspects of mental disorders will yield new and better targets for treatment

Question 37

RDoC approach to classifying psychosis

Answer 37

Recruited individuals with either schizophrenia, schizoaffective disorder and bipolar disorder with psychosis, their first degree relatives and controls Performed a series of tasks that assess brain function at the neurocognitive/perceptual Lebel 3 subsets of biomarkers differentiated groupings of psychosis cases from each other considerably better than traditional clinical diagnoses The biotypes were more biologically homogenous than categories based on observable symptoms Differences in brain structure also distinguish the three biotypes, further validating the categorisations

Question 38

trial and error approach to treatment burdens families

Answer 38

Disruption to routine and home environment Parents not sure whether outcome is worth risks Cost attending appointments and long wait times (difficult when needing to make changes to medication)

Question 39

current treatment of ASD

Answer 39

Currently no approved treatments core symptoms of autism: social difficulties, repetitive behaviours Often treating comorbid symptoms (anxiety, depression, hyperactivity, aggression), not core ASD symptoms 1 in 3 take some type of psychotropic mediation. 1 in 10 take 3+ medications

Question 40

current treatment of ADHD

Answer 40

Stimulants remain first line psychopharmacological treatment: 70-80% respond to stimulant medication. Parents want to know if their child is part of the 20-30% who don’t respond Much longer history attempting to identify predictors of treatment response: e.g. attention span, baseline symptom severity, theta/beta EEG ratios, ERPs (P300, N2), candidate gene approach

Question 41

genetic guidance tools

Answer 41

Using a variety of genetic markers to predict treatment outcomes (liver metabolising genes, blood brain barrier genes, CNS genes) Outcomes measured by: response to treatment, chance of adverse outcomes

Question 42

RDoC and the future of PGx for neurodevelopment disorders

Answer 42

Acknowledges the biological and genetic origins of neurodevelopment disorders A future for diagnosis and treatment based on the causation of a disorder rather than symptoms alone Optimising drug selection and dosing based on genetic information, with objective measures to help inform treatment response Improves diagnostic reliability, speed of diagnosis, and prediction of treatment outcomes