autism Flashcards
what is difference between neurodegenerative disease and neuropsychiatric disease
in degenerative disease is progressive and nerve cells degenerate and die
in psychiatric disease, disease is mostly not progressive and cells do not degenerate/die
what is the autistic diad
what constitutes autism; defects in social interaction
and restricted interests and repetitive behaviours
how is gender related to autism
males more commonly affected; 4:1
what are core elements of ASD
impaired joint attention, avoids social interaction (happiest playing alone), avoids eye contact, difficulty making friends, difficulty understanding what others are thinking and feeling
restricted and obsessive interests and behaviours characterise ASD (if not present it is not ASD)
strong preference for sameness, repitition and predictability
what are common but variable features of ASD
language delay and impairment
various behavioural abnormalities ; eating, sleeping, irritability and tantrums
abnormal motor control
abnormal sensitivity to light
mental retardation
seizures
social regression (most develop normally in first year, 20-30% show dramatic regression in second year), most if not all show some regression
savant skills; are isolated special abilities which involve things such as memory, calculation, drawing, they are common however prodigious savants are ones with extraordinary skills but are rare
how ASD frequency changed over time
large increase in ASD frequency recently however this may be accounted for by broadening of diagnostic criteria (to include aspergers), improved diagnosis, increased awareness, reduced stigma and special educational services for ASD children
risk of ASD increases with increased father age, so late parentage may contribute a little
how does postnatal environment contribute to ASD
no evidence that postnatal environmental factors increase risk of ASDs
however stresses in utero can increase risk (e.g maternal drugs or infection)
describe genetic factors in ASD
identical twins show 80-90% concordance for ASD, non identical twins and siblings show 10-20%
2 types of genetic risk factors for disease; common gene variants/polymorphisms and rare mutations
common gene variants/polymorphism have small effect on risk
rare mutations have big effect on risk, mainly identified as copy number variants
rare mutations include neuroligins and shanks
common variants include CDH9 and CDH10
some forms of autism are caused by single gene mutations; monogenetic syndromic forms, these account for roughly 4% of ASDs and almost all are caused by de novo mutations
what are examples of monogenetic syndromic forms of ASD
Rett syndrome; MECP2 gene on X chromosome, encodes a protein that binds to methylated cytosines in DNA, most Rett girls are autistic but also have various other neurological problems
mutant (no MECP2) boys die in first year or 2, in girls X inactivation means that some cells have MECP2 and some dont, girls develop normally and then regress in second year, lose speech, congitive decline and develop autism and motor defects, after regression girls improve a little and live a normal lifespan
rett mouse models; males develop signs at 6 weeks and die by 10 weeks, females develop normally till 4-10 months, then they regress, then improve a little and live a normal lifespan
MeCP2 gene can be knocked out in adult and develop rett-like symptoms, showing it is not developmental
tuberous sclerosis; TSC1 or TSC2 genes, encode a protein complex that inhibits an intracellular signalling pathway, 40% are autistic
fragile X syndrome; FRM1 gene, encodes a protein that regulates protein synthesis at the synapse,30% are autistic
how might mutations in ASD lead to physiological differences
decrease in size and number of dendritic spines in ASD
mutations in neuroligin3 or neuroligin4 is associated with autism, these have x-linked genes which encode cell adhesion proteins that act only at synapses, they are required for synapse maturation and normal synaptic function
mutations in NLGN4,NRXN1 and SHANK3 are found in roughly 3% of ASDs
how do the same mutations affect ASD
same mutation in same familyt can give either end of ASD spectrum (except monogenetic syndromic types)
how do copy number variants effect ASD
copy number variants: changes in number of copies of DNA from expected values (usually 2 alleles), results from deletion or duplication of a relatively large genomic region (containing multiple genes), changes “dosage” of one or more genes which effects disease, rare CNVs are established risk factors for psychiatric disorders
what models are used in ASD research
mouse models can be used to determine which cell types, brain areas and synapses and circuits are affected by big effect mutations
how are pluripotent stem cells used in ASD research
skin tissue is expanded in vitro, converted to fibroblasts which are reprogrammed into pluripotent stem cells which are converted to neural progenitors via neural induction, which using neural patterning can be used to make forebrain tissue
forebrain tissue can be converted into glutamatergic cortical projection neurones by down regulation of sonic hedgehog or into GABAergic cortical interneurones by upregulation of sonic hedgehog
they are then transplanted into mouse cortex to investigate if they integrate, can they fire APs and do they generate synapses
in phelan mcdermid syndrome neurones have impaired excitatory synaptic transmission, show reduced expression of glutamate receptors and decreased numbers of synapses, reduced SHANK3 expression contributes to these synaptic defects, IGF1 treatment restores excitatory synaptic transmission in PMDS neurones
