Lecture 12: Intellectual Disability Flashcards
What is the traditional view of neurodevelopmental disorders?
three types:
autism spectrum disorder (ex autistic disorder, Asperger’s syndrome)
intellectual disability (ex. down syndrome, fragile X syndrome)
other developmental disorders (ex. ADHD, learning disabilities)
What is the novel view of neurodevelopmental disorders?
neurodevelopmental disorders in the DSM-5: intellectual disabilities, autism spectrum disorder, ADHD, schizophrenia, bipolar disorder
hypothetical genetic neurodevelopmental continuum
genetic overlap between NDD and mental health
What does intellectual disability refer to?
a group of disorders where children fail to develop normal cognitive skills including: language, activity of daily living, learning and memory, etc.
different causes: genetic, environmental, drugs, brain malformation
can be inherited or sporadic (de novo)
What are the statistics associated with intellectual disability?
ID affects 3% of the population
ID leads to cost of $1.3 billion each year in Canada
ID is diagnosed between 3 and 9 years old and affects the patient for life
What other conditions are associated with intellectual disability?
obsessive compulsive disorder
sleep defects
anxiety
sensory processing defects
epilepsy
autism
general mental ability
defects in adaptive function
onset in developmental period
What is the familial impact of intellectual disability?
in the recent international FXS survey, 60% of parents of children with FXS report an excessive financial burden
40% of parents having to leave employment to care for the affected child
over 60% having to reduce their working hours
only 10% of adult males with FXS can live independently as adults
What is the controversy surrounding “curing” intellectual disability?
parents of children with Down’s syndrome found that most (61%) had a positive view of treatment possibilities but only 41% would “cure” their child if possible
focus on “cures” may distract us from policies to improve social accommodation and acceptance or result in a loss of “neurodiversity” that is socially positive
unproven therapies for autism, for example, are being globally marketed, are often linked to emerging areas of science and are driven by inaccurate media representations of the supporting evidence and science
social media has also played a significant role in the spread of exaggerated or false claims
What are the techniques used to investigate individuals with intellectual disability?
- assess the developmental milestones: scales have been developed to monitor the development of children and the acquisition of new skills
- psychometric testing: looks at intelligence, problem solving, planning, looks at many areas
- neuroimaging can be performed on living patients at multiple times (MRIs): imaging abnormalities are common in ID
- DNA analysis: from chromosomes to single base
What are the measures of theoretical intelligence?
general mental capacity
ability to reason
solve problems
think abstractly
plan
What are the measures of objective intelligence?
IQ
Who was Alfred Binet?
psychologist
developed testing of various mental functions to help schooling of children
test would give the mental age
worked with Charcot and then at Sorbonne
What is IQ testing?
verbal and non-verbal (visuo-spatial) components
IQ are normally distributed in the population
IQ is relative to children of the same age
How is DNA analysis used to test for intellectual disability?
next-generation sequencing has a single base pair resolution
allows to identify single base pair changes in the DNA sequence of the exons or can be applied to entire genome
genome wide approaches: CNVs and SNVs testing allowed to identify increasing number of individuals with multiple mutations
What is down syndrome?
down syndrome is the most common cause of intellectual disability in the whole population
caused by the trisomy of chromosome 21 (in part or entirely)
no treatment known
What is the definition of a syndrome?
common association of certain symptoms in the history of the patient and certain signs in patient examination
What is fragile X syndrome?
most common ID in males (1:4000) but also affects females (1:8000)
dysmorphic features (large ears)
epilepsy (30%)
visuospatial memory defects
autism (60%)
the FX syndrome was initially found on karyotype
abnormal synapses: in fragile X the dendritic spines are more immature (long/thin)
What is Rett syndrome?
common cause of intellectual disability in girls
apraxia
breathing problems
shaky, unsteady, or stiff gait
slowing head growth beginning at approximately 5-6 months of age
loss of purposeful hand movements
loss of normal sleep patterns
caused by MeCP2 mutation
What is the MeCP2 protein?
MeCP2 regulates epigenetic
complex binds to DNA to silence transcription
if you don’t have MeCP2, then some genes will be transcribed that shouldn’t or genes that need to be transcribed won’t be
What is the treatment for intellectual disability?
no current approach targeted treatment
we use symptom based management (stimulants for ADHD, SSRI for anxiety, antipsychotic for behavior issues)
never use drugs without intervention or therapy
What is the traditional model of drug discovery?
find patients and identify gene
develop a fly, mice, c. elegans, rat model, induced pluripotent stem cells derived neurons
identify candidate drug
test in randomized clinical trail
What is the new model of drug discovery?
patient based
co-development
identification of target behavior with patients and families
pharmacogenetics
develop models focused on patients’ priorities
identify candidate drugs
novel trial approaches (N of 1, basket trials)
What is the novel approach to treating intellectual disability?
- identify the target phenotype: many times phenotypes to be targeted have been decided by MD or companies, sometimes based on animal model even, we need to consult with families and patients
- multiple dimensions to consider for clinical trials
- translational science: animal models can help identify candidate drugs by modelling phenotypes associated with patient symptoms, but we need to remember differences with humans (hybrid approach)
What factors influence drug or gene dosage effect on phenotype?
demographics (age, sex, gender, genetic background)
brain region (cerebellum, amygdala, hippocampus, cortex)
cell type
pre and post synaptic signaling
cellular gene expression (tissue specific, age dependent, sex dependent)
other medical conditions
other drugs
How are flies used as a model for intellectual disability?
they also have 85% of the genes involved in neurological disorder
brain shape can be different and still show conservation in behavior
How was metformin shown to be a treatment for FXS?
classical olfactory conditioning in flies follows the same paradigm that Pavlov did, an odor is presented at the same time as a foot shock
impaired protein synthesis dependent memory in dfmr mutants
IS based rescue of memory in fmr1
metformin rescues memory defect in FXS
metformin rescues LTD and ERK signaling in FMR1KO mice
pilot trials in patients can help identify candidate molecules
validation required randomized controlled trials, require multicentric trials
How are outcome measures chosen?
outcomes measure relevant to the patients are important
outcome measures related to animals are also important
outcomes measure done online are easier to administer
What is expressive language sampling?
conversation: examiner talks with the participant using a script with selected topics
narrative: participant tells the examiner the story from a wordless picture book
primary outcome measure
What techniques are used to understand intellectual disability?
history and physical (IQ testing, multidisciplinary teams)
imaging (CT, MRI)
genetic (karyotype, CGH, sequencing)
What are common causes of intellectual disability?
brain malformations (found on MRI)
genetic causes: down syndrome, fragile X, new syndromes found by genome-wide testing
