Module IV - Lecture 4 - Autism

Question 1

What makes up 10% of ASD cases?

Answer 1

savant syndrome - savant like abilities
i.e. name an day of the week for any given date, draw city line from memory, recite digits of pi

Question 2

What are the core symptoms of ASD?

Answer 2

social deficits
language impairment
repetitive behaviors

Question 3

What are the comorbid symptoms of ASD?

Answer 3

sleep deficits
anxiety
hyperactivity
attention
seizures
mood

Question 4

50-60% of people with ASD also display what?

Answer 4

intellectual disability

Question 5

ASD affects what percent of the population?

Answer 5

1%
neurodevelopmental disorder
age on onset is between 6 months - 2yo

Question 6

What is asperger syndrome?

Answer 6

-used to describe individuals who exhibit the typical features of autism but have high verbal ability and no delay in acquisition

Question 7

When do mutations for ASD start?

Answer 7

late prenatal or early postnatal development

Question 8

What are some examples of social deficits?

Answer 8

-creatures of habit and have routines
-obsessed and talk about one topic
-repeat thing other people say
-like to spin and stack objects
-in small cases can do things very well
-hyper and hyposensitivity to smells tastes and textures and sounds

Question 9

What happens with individuals with ASD and eye contact?

Answer 9

do not look into the eyes of other and they are not interested in making eye contact lack social cues

Question 10

Is there a strong genetic component to this disease?

Answer 10

-yes there is a very large discrepancy between concordance between monozygotic and dizygotic twins
-the concordance can be up to 91% FOR MONOZYGOTIC TWINS IF FULL SPECTRUM OF ASD IS CONSIDERED WHILE DIZYGOTIC IS 15% - VERY GENETIC ROLE

Question 11

What brain areas are implicated in three core deficits characteristics of autism?

Answer 11

social deficits - orbitofrontal cortex, anterior cingulate cortex, amygdala, fusiform gyrus, superior temporal sulcus (gaze perception), fusiform gyrus (face processing)

comprehension of language - pontine nuclei

repetitive behaviors - striatum
(repetitive behaviors are easy to study in preclinical models - ASD genetic models groom themselves compulsively for striatum)

Question 12

What are the characteristics of fragile x syndrome for males?

Answer 12

-prominent or long ears
-a long face
-delayed speech
-large testes (macroorchidism)
-hyperactivity
-tactile defensiveness (do not like to be touched)
-gross motor delays
-autistic-like behaviors

Question 13

Are the symptoms milder or more extreme in females for fragile x syndrome?

Answer 13

symptoms milder in females

Question 14

What causes fragile x syndrome?

Answer 14

a mutation in the FMRP gene on the x chromosome

Question 15

What is a monogenetic form of ASD mutation in a single gene?

Answer 15

fragile x syndrome and this is a mutation in the fmrp gene and is more likely in men cause they only have one x chromosome cause the male has only one copy of the fmrp and in females they have two copies so this much milder

Question 16

What gene is involved in the fragile x syndrome?

Answer 16

FMR1 gene

Question 17

What does the FMR1 gene encode?

Answer 17

FMRP protein

Question 18

What does the FMRP protein do?

Answer 18

it binds to mRNA and prevents protein translation

Question 19

If FMRP is not functional in Fragile X patients what happens?

Answer 19

leading to the upregulated expression of many genes
-we do not know what upregulation of genes causes fragile x associated behavioral phenotypes - think it may be implicated the upregulation of proteins in endocytosis of AMPARs are causing the weakening of these synapses

Question 20

What is the mutation in the FMR1 gene?

Answer 20

-there are a series of repeats of CGG and between 6 and 54 repeats CGG is normal but in fragile x syndrome there is an expansion of the CGG repeat region and this happens in blastocysts when chromosomes are dividing so these people can have over CGG repeats and this gene due to the repeats the RNA polymerase trying to read his cannot get through the repeats and it stalls put and the mRNA for the FMRP is not produced so do not get the FMRP protein from getting made

Question 21

What does the loss of FMRP function result in?

Answer 21

glutamatergic synapses in the brain - get augmentation of endocytosis of ampa receptors and weakening of synapses

Question 22

What is Rett syndrome?

Answer 22

in girls and women and one in 10,000 and 15,000 girls and loss of hand movements and speech and balance and coordination and walking and lose all walking in 0% and breathing problems and apnea and hyperventilation and anxiety disorder

Question 23

What gene mutation causes Rett syndrome?

Answer 23

MeCP2 gene mutations on chromosome x and the syndrome is not seen in males typically because male infants die from lack of a functional MeCP2 gene

Question 24

What does the MeCP2 gene regulate?

Answer 24

gene transcription in many ways
-transcriptional repression
-transcriptional activation
-chromatin compaction
-chromatin loop formation (can form a hairpin so that it can bring two genes close together)
-we do not know what specific gene transcription gets affected by MeCP2 gene gives rise to Rett syndrome

Question 25

What drug has been found to treat Rett syndrome?

Answer 25

trofinetide - it is an igf1 analog which individuals with Rett syndrome have a reduction in a glutamatergic synapse - this igf1 analog increases glutamatergic synapses density

Question 26

How many ASD associated risk genes are there?

Answer 26

-over 200 associated genes and these genes have a significant amount of ASD genes which encode transcriptional regulators and if you screw up one TF influence the transcription of a bunch of other genes - what cellular process is being compromised among all of these individuals and this is likely convergence point so these individuals with and have issues with glutamatergic synapse formation -shank is here and trio is here -enrichment of ASD related mutations in genes encoding transcriptional regulators

Question 27

What phenotypes are associated with neurodevelopmental and neuropsychiatric disorders?

Answer 27

-sometimes ASD related mutations cause fewer glutamatergic synapses -sometimes ASD related mutations cause too many glutamatergic synapses -very diverse array in glutamatergic synapses in ASD

Question 28

What are GEF proteins at glutamatergic synapses?

Answer 28

kalirin and trio

Question 29

Are there more ASD-associated de novo mutations in Trio?

Answer 29

5000 genes in which one person has it -trio is in the top 10%

Question 30

Where are ASD-associated mutations clustered in Trio?

Answer 30

the GEF1 domain (SNPs)

Question 31

What does the GEF1 domain of trio do?

Answer 31

bind to Rac1 to promote actin polymerization

Question 32

Where are trio mutations in people with no ASD found?

Answer 32

not found in the GEF1 domain

Question 33

What are ASD-associated mutations in Trio's GEF1 domain predicted to cause?

Answer 33

inhibition of the GEF function and mutations cause issues in rac1 associating with trio

Question 34

What are ASD-associated mutations in Trio's GEF1 domain alter; how do we know this?

Answer 34

glutamatergic synapse function; overexpress trio in neurons the neurons get stronger- overexpress broken trio with mutation in gef1 domain then there is reduction in trio function and this causes smaller and weaker synapses to see if normal and broken copy can compete and outcompete trio that is not broken

Question 35

What trio mutation is abnormally synptogenic?

Answer 35

D1368V - it allows neuroligin to make more synapses if you increase trio function causing more nmda current

Question 36

What does the D1368V mutations prevent and how does this do this; what disease is this knwon as?

Answer 36

autoinhibition of Trio's GEF1 domain - trio folds back omn itself and the eight spectrum repeat that folds back and binds to gef1 autoinhibits its function and this mutation prevents that so it is tonically active -TRIO syndrome

Question 37

How many ASD related mutations are there in kalirin and why?

Answer 37

0 mutations - this is due to the fact the trio expression is high early postnatal and then later on as you develop it goes down and kalirin expression is low when you first develop and then goes up

Question 38

Can genetic intervention be used to correct ASD related behavioral phenotypes later in life?

Answer 38

use of genetic tricls to make a mouse that is misisng a copy of shank3 and can come in with drug later aka tamoxifen and this would cause the missing exon to flip nack and ve restroed and see you can fix behvaioral issues these mice had - these KO shank3 mice had repetitive grooming, social interaction deficits, increased anxiety and motor deficits -trun shank3 back on at 2-4.5 motnhs restored the glutamnatergic synapse function and rescued repetitive grooming, social interaction deficit - did not rescue anxiety and motor deficits -but if rescued shank3 ealrier like postnatal 20-21 days can rescue anxiety and motor deficits too

Question 39

Does it matter when you give the trofinetide to rett syndrome earlier?

Answer 39

yes - helps more in mitigating body rocking and facial expressions and alleviating anxiety and breathing problems to a greater extent the younger you are when you receive the drug