Neurodevelopmental syndromes and ASD Flashcards
FXS is the
Most frequent monogenic cause of autism
FXSis a genetic disease that
Causes a range of developmental problems including learning disabilities and cognitive impairment
Features of FXS
Long and narrow face Large ears Prominent jaw and forehead Flat feet Macroorchidism
FXS is diagnosed by
Blood test
Molecular basis of FXS
CGG trinucleotide expansion repeats at gene locus Xq27.3 causing alteration in FMR1 gene
Normal/ healthy CGG trinucleotide expansion repeat
6-55
mRNA produces FMRP
Premutation CGG trinucleotide expansion repeat
55-200
May show mild cognitive and motor deficits in old age
Abnormal CGG trinucleotide expansion repeat
Full mutation over 200-1000 repeats
No mRNA, no protein
Shown in western blot
Evidence of FXS
Use drosophila model
Advantage to drosophila model
No licence required and short generation time
Drosophila gene used..
dFMR1 which is the orthologue of FMR1
Study social interaction of drosophila (impaired in ASD)
Courtship
Forward to female and tapping, vibrating and copulation
Dockendorff et al 2002
Looked at WT and mutant flies with mutation in dFMR1 gene
Dockendorff et al 2002 courtship assay
10 min assay with virgin female and 5 day old male mutant
Dockendorff et al 2002
courtship assay
RESULTS
Mutant animals showed sig less courtship than WT and spent sig less time engaged in active courtship
More time spent in forward tapping phase
Same in immature males - no courtship in mutant
Conclusion of Dockendorff et al 2002 assay
Less social interaction of the mutants
Advantages to Dockendorff et al 2002 assay
Cheap to keep, quick generation interval, brain autopsy
Disadvantages to Dockendorff et al 2002 assay
Too different from humans
Sequence identity between FMR1 and dFMR1 is low
Tuberous sclerosis complex is..
associated with ASD
Causes mainly benign tumours to develop in different parts of the body
Behavioural problems such as ASD
TSc ranges from mild to severe
Autosomal dominant rare genetic disease that affects
1 in 6000 people
Prevalence of ASD in TSC patients
Vignoli et al 2015
High prevalence
40%
Symptoms of TSC
Dermatological manifestations e.g. leaf spots
Neuropsychiatric symptoms
Cortical tumours- benign tissue growth replace normal tissue, disrupts highly organised neurological connections of the cerebral cortex
Enclosed in skull squeezing and displacing other part of brain
Molecular basis of TSC
Single gene mutation in TSC1 (hamartin) or TSC2 (tuberin)
Usually tumour suppressors regulating mammalian target of rapamycin (mTOR) signalling pathway
Mutations of TSC1 and 2 cause..
Hyperactivation of the pathway causing abnormal cell growth, proliferation and tumourgenesis
Uncontrolled pathway
Link of TSC to ASD demonstrated by
Jeste et al 2014
Jeste et al TSC study
40 infants with TSC included
Autism observation scale at 6, 9, 12 and 18 months
Diagnostic observation schedule at 18, 24 and 36 months
Jeste et al 2014 results
55% diagnosed with ASD
Usefulness of AOSI as a measure of ASD behaviour evaluated by Capal et al 2017
Found it useful clinical tool in determining which infants with TSC are at increased risk for developing ASD
Activity Dependent Neuroprotective Protein syndrome
Complex neurodevelopmental disorder that affects the brain and many other areas and functions of the body
ADNP syndrome patients have
Mild to severe delays in intelligence, speech and global motor planning
Causes behaviour disorders e.g. ASD
Molecular basis of ADNP syndrome
Caused by de-novo ADNP brain gene (locus 20q13.13) mutation found by Helsmoortel et al in 2014
ADNP is
Vasoactive intestinal peptide responsive gene
ADNP gene normally..
Important in brain function and development as well as protecting nerve cells against electrical blockage
Aetiology of ADNP
Uncertain but thought that abnormal gene product competes with WT to bind to BAF(?) complexes
Arnett et al 2018
Examined the ASD phenotype in sample of representative youth with ADNP disruption
Arnett et al 2018 found..
AMong individuals with a mutation to ADNP 64% met DSM-5 diagnostic criteria for ASD
Reported ASD symptoms among youth ascertained for ADNP syndrome are characterised by relatively mild social communication deficits
