Lecture 12: Intellectual Disability

Question 1

What is the traditional view of neurodevelopmental disorders?

Answer 1

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)

Question 2

What is the novel view of neurodevelopmental disorders?

Answer 2

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

Question 3

What does intellectual disability refer to?

Answer 3

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)

Question 4

What are the statistics associated with intellectual disability?

Answer 4

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

Question 5

What other conditions are associated with intellectual disability?

Answer 5

obsessive compulsive disorder
sleep defects
anxiety
sensory processing defects
epilepsy
autism
general mental ability
defects in adaptive function
onset in developmental period

Question 6

What is the familial impact of intellectual disability?

Answer 6

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

Question 7

What is the controversy surrounding “curing” intellectual disability?

Answer 7

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

Question 8

What are the techniques used to investigate individuals with intellectual disability?

Answer 8

1. assess the developmental milestones: scales have been developed to monitor the development of children and the acquisition of new skills
2. psychometric testing: looks at intelligence, problem solving, planning, looks at many areas
3. neuroimaging can be performed on living patients at multiple times (MRIs): imaging abnormalities are common in ID
4. DNA analysis: from chromosomes to single base

Question 9

What are the measures of theoretical intelligence?

Answer 9

general mental capacity

ability to reason

solve problems

think abstractly

plan

Question 10

What are the measures of objective intelligence?

Answer 10

IQ

Question 11

Who was Alfred Binet?

Answer 11

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

Question 12

What is IQ testing?

Answer 12

verbal and non-verbal (visuo-spatial) components

IQ are normally distributed in the population

IQ is relative to children of the same age

Question 13

How is DNA analysis used to test for intellectual disability?

Answer 13

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

Question 14

What is down syndrome?

Answer 14

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

Question 15

What is the definition of a syndrome?

Answer 15

common association of certain symptoms in the history of the patient and certain signs in patient examination

Question 16

What is fragile X syndrome?

Answer 16

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)

Question 17

What is Rett syndrome?

Answer 17

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

Question 18

What is the MeCP2 protein?

Answer 18

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

Question 19

What is the treatment for intellectual disability?

Answer 19

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

Question 20

What is the traditional model of drug discovery?

Answer 20

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

Question 21

What is the new model of drug discovery?

Answer 21

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)

Question 22

What is the novel approach to treating intellectual disability?

Answer 22

1. 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
2. multiple dimensions to consider for clinical trials
3. 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)

Question 23

What factors influence drug or gene dosage effect on phenotype?

Answer 23

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

Question 24

How are flies used as a model for intellectual disability?

Answer 24

they also have 85% of the genes involved in neurological disorder

brain shape can be different and still show conservation in behavior

Question 25

How was metformin shown to be a treatment for FXS?

Answer 25

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

Question 26

How are outcome measures chosen?

Answer 26

outcomes measure relevant to the patients are important

outcome measures related to animals are also important

outcomes measure done online are easier to administer

Question 27

What is expressive language sampling?

Answer 27

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

Question 28

What techniques are used to understand intellectual disability?

Answer 28

history and physical (IQ testing, multidisciplinary teams)

imaging (CT, MRI)

genetic (karyotype, CGH, sequencing)

Question 29

What are common causes of intellectual disability?

Answer 29

brain malformations (found on MRI)

genetic causes: down syndrome, fragile X, new syndromes found by genome-wide testing