Week 5 Flashcards
By studying gene-behaviour relationships in neurodevelopment disorders that have a strong genetic origin we can:
Improve diagnostic reliability
Reduce time to diagnosis
Tease apart the causes of problem behaviours
Develop sensitive and appropriate treatment options
neurodevelopmental disorders
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)
single gene disorder examples
fragile x, Williams syndrome
polygenic disorder examples
ASD, ADHD
genes
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
alleles
variants of a gene
SNP
variation in a single nucleotide that occurs at a specific point in the genome
fragile x
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
fragile x treatment
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
polygenetic disorders
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
heritability
Amount of variation in a phenotypic trait in a population that can be attributed to genetic variation among the members of that population
phenotypic trait
obvious and observable trait
genetic variation
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
how do we estimate heritability
Parents to offspring
Comparing siblings
Comparing twins (identical and non identical)
broader autism phenotype
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
ADHD
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
diagnosing ADHD
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
ADHD symptoms divided into
inattention
hyperactivity/impulsivity
ADHD treatment
Main treatment is stimulant medication: methylphenidate and dexamphetamine
Non stimulants such as atomoxetine also used
Stimulants effect size is greater than non stimulants
methylphenidate ADHD
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)
candidate gene
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
DAT1
one allele of this gene is associated with excessive reuptake of dopamine, leading to under activity in dopamine pathways
DRD4
one allele is associated with a sub sensitive post synaptic receptor (not as sensitive to dopamine)
Associations between DAT1 and attention
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
ASD
Highly heritable
Classified according to DSM-5 criteria: core deficits in 1. Social communication/interaction and 2. Restricted and repetitive behaviours
behaviour ASD
poor sensory integration, ‘local information bias’
neuropathology ASD
cortical minicolumns, reduced connectivity between cortical areas
candidate genes ASD
CNTNAP2, SHANK3, neurexin, reelin
classic symptoms ASD
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
EN2 and formation of the human cerebellum
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
epigenetics
Study of how gene activity is regulated, and how genes are expressed, independent on an individual’s genetic sequence
Gene-behaviour relationship in ASD
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
How we study behaviour-brain-gene relationships
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)
limitations of current approach to diagnosis
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.
little success finding genetic causes for neurodevelopment disorders
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)
RDoC
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
RDoC approach to classifying psychosis
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
trial and error approach to treatment burdens families
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)
current treatment of ASD
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
current treatment of ADHD
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
genetic guidance tools
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
RDoC and the future of PGx for neurodevelopment disorders
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
