Module IV - Lecture 4 - Autism Flashcards
What makes up 10% of ASD cases?
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
What are the core symptoms of ASD?
social deficits
language impairment
repetitive behaviors
What are the comorbid symptoms of ASD?
sleep deficits
anxiety
hyperactivity
attention
seizures
mood
50-60% of people with ASD also display what?
intellectual disability
ASD affects what percent of the population?
1%
neurodevelopmental disorder
age on onset is between 6 months - 2yo
What is asperger syndrome?
-used to describe individuals who exhibit the typical features of autism but have high verbal ability and no delay in acquisition
When do mutations for ASD start?
late prenatal or early postnatal development
What are some examples of social deficits?
-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
What happens with individuals with ASD and eye contact?
do not look into the eyes of other and they are not interested in making eye contact lack social cues
Is there a strong genetic component to this disease?
-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
What brain areas are implicated in three core deficits characteristics of autism?
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)
What are the characteristics of fragile x syndrome for males?
-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
Are the symptoms milder or more extreme in females for fragile x syndrome?
symptoms milder in females
What causes fragile x syndrome?
a mutation in the FMRP gene on the x chromosome
What is a monogenetic form of ASD mutation in a single gene?
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
What gene is involved in the fragile x syndrome?
FMR1 gene
What does the FMR1 gene encode?
FMRP protein
What does the FMRP protein do?
it binds to mRNA and prevents protein translation
If FMRP is not functional in Fragile X patients what happens?
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
What is the mutation in the FMR1 gene?
-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
What does the loss of FMRP function result in?
glutamatergic synapses in the brain - get augmentation of endocytosis of ampa receptors and weakening of synapses
What is Rett syndrome?
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
What gene mutation causes Rett syndrome?
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
What does the MeCP2 gene regulate?
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
What drug has been found to treat Rett syndrome?
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
How many ASD associated risk genes are there?
-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
What phenotypes are associated with neurodevelopmental and neuropsychiatric disorders?
-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
What are GEF proteins at glutamatergic synapses?
kalirin and trio
Are there more ASD-associated de novo mutations in Trio?
5000 genes in which one person has it
-trio is in the top 10%
Where are ASD-associated mutations clustered in Trio?
the GEF1 domain (SNPs)
What does the GEF1 domain of trio do?
bind to Rac1 to promote actin polymerization
Where are trio mutations in people with no ASD found?
not found in the GEF1 domain
What are ASD-associated mutations in Trio’s GEF1 domain predicted to cause?
inhibition of the GEF function and mutations cause issues in rac1 associating with trio
What are ASD-associated mutations in Trio’s GEF1 domain alter; how do we know this?
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
What trio mutation is abnormally synptogenic?
D1368V - it allows neuroligin to make more synapses if you increase trio function causing more nmda current
What does the D1368V mutations prevent and how does this do this; what disease is this knwon as?
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
How many ASD related mutations are there in kalirin and why?
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
Can genetic intervention be used to correct ASD related behavioral phenotypes later in life?
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
Does it matter when you give the trofinetide to rett syndrome earlier?
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
