Autism Flashcards
Fragile X syndrome is the
Most frequent monogenic cause of ASD (Bailey et al)
FXS is a genetic disease that..
Causes a range of developmental problems:
Learning difficulties and cognitive impairment
Males are more severely affected than females as
X-linked
Features of FXS
Long narrow face, large ears, flat face and macroorchidism in males
Diagnosed by blood test
FMRP1
Most FXS patients show ASD
Affect communication and social interaction
Molecular basis of FXS
CGG trinucleotide expansion repeat
Gene locus for FXS
X q27.3 alteration in FMR1 gene
Normal healthy
6-55 repeats (mRNA produced from FMRP)
Premutation
55-200 repeats
May show mild cognitive impairment and motor defects in old age
Abnormal mutation
More than 200 to 1000 repeats
No mRNA no protein
Evidence with use of drosophila orthologue
dFMR1
Orthologue looks at
Sex-relevant to ASD as it involves social interaction
Drosophila model looks at
Courtship behaviour Forward to female Tapping Vibrating Copulation
Dockendorff et al 2002
10 min courtship assay with virgin female and 5 day old mutant male
Dockendorff mutants show
Sig less courtship than WT animals
Spent sig less time in active courtship
More in forward tapping phase
Same in immature male- no courtship in mutant
Advantages of Dockendorff
Cheap, quick generation interval and brain autopsy
Disadvantages of Dockendorff
Sequence identity between FMR1 and dFMR1 too low
Tuberous Sclerosis Complex (TSC)
Leads to some forms of ASD - behavioural problems
TSC causes
Benign tumours to develop
Type of disorder TSC
autosomal dominant
1 in 6000
Vignoli et al 2015
ASD prevalence in TSC = 40.5%
Cortical tumours in TSC
Benign tissue growth replacing normal tissue disrupting highly organised neurological connection of cerebral cortex
Enclosed in skull, displace parts of brain
Molecular basis of TSC
Single gene mutation in TSC1 (hamartin) or TSC2 (tuberin)
TSC1 and TSC2 are
Usually tumour suppressors
Regulating the mammalian target of rapamycin (mTOR) signalling pathway
Mutations in TSC1 and TSC2 ..
Hyperactivation of pathway causing abnormal cell growth and tumourgenesis uncontrolled pathway
Evidence for TSC
Jeste et al 2014
40 infants with TSC in longitudinal cohort study
6,9,12 and 18 months autism observation scale
18,24, 36 months Diagnostic observation scale
Jeste et al 2014 what percentage were diagnosed with autism
55%
Autism observation scale was evaluated by
Capal et al 2017
found it a useful clinical tool in determining which infants were at increased risk of ASD
Activity dependent neuroprotective protein (ADNP)
Complex neurodevelopmental disorder that affects the brain and many other areas/ functions of the body
ADNP causes mild to severe delays in
Intelligence, speech and global motor planning
Causes behavioural problems such as ASD
Molecular basis of ADNP
Caused by non-inhertied (de novo) ADNP gene 20q13.13 mutation
Who discovered ADNP
Helsmoortel et al 2014
What is ADNP
Vasoactive intestinal peptide responsive gene
Important in brain function and development as well as protecting cells against electrical blockade
Uncertain theory of ADNP
Thought that abnormal gene product competes with WT to bind to BAF complex
Arnett et al 2018 evidence for ADNP
Examined ASD phenotype in samples of youth with ADNP
64% met DSM-5 criteria for ASD
Reported ASD symptoms ascertained for ADNP syndrome and characterised by relatively mild social communication deficits
16p11.2 deletion syndrome
most frequent genetic mutation observed in ASD (Weiss et al 2008)
Deletion mutation
Part of a chromosome or sequence of DNA that is lost during DNA replication
Deletion or duplication of 1 copy of 16p11.2 is associated with
Impaired brain function and ASD
Ciuladaitc et al 2011
What percent of ASD patients have 16p11.2
0.44%
All patients with 16p11.2 mutation show
Macrocephaly and flat midface
Mean head circumference for deletion was sig larger than population mean
Zebrafish model of 16p11.2 genome include homologs of human gene
84%
Baker-Lee et al 2012
Morpholinos
Block splicing or translation of a specific mRNA
Resulting in decrease or even lost expression of the respective gene product
Use morpholinos in 16p11.2 to..
known down kctd13 by ~70% sig increase in head size
Zebrafish model of 16p11.2 doesn’t
Exclude other possibilities that other genes in human region of 16p11.2 also contribute to head size
Social housing experiment Yang et al 2015
Explore role of social housing environment in the development of social and cognitive phenotypes
Yang et al 2015 testes 16p11.2
Heterozygotes with cagemates of the same genotype and those with opposite genotype
Phase 1 of Yang et al 2015 social housing
Mouse put in arena with other mouse in the cylinder
WT is more interested in mouse than empty cylinder
Phase 2 of Yang et al 2015 social housing
Measure preference for social novelty/ memory
Stranger put in, WT moves attention to new mouse
Yang et al 2015 found that same genotype..
Showed sig decrease in exploration of +/- in arena exploration and in mixed genotype
Sig decrease in front approach in same genotype
Object location memory Yang et al 2015
+/- were 50% smaller than +/+
Become subordinate animals
Low social status affect cognitive function
mGluR5 theory of FXS
Excessive protein synthesis of synaptic plasticity gating proteins occur due to mGluR5 activation
Due to absence of FMRP
Treatment with mGLuR5
Use inhibitor of mGluR5 mPEP to treat
McBride et al 2005 - administered to flies (8.6um) for 4 days
Didnt reduce mushroom lobe fusion
Therefore doesnt work
