Neurodevelopmental syndromes and ASD

Question 1

FXS is the

Answer 1

Most frequent monogenic cause of autism

Question 2

FXSis a genetic disease that

Answer 2

Causes a range of developmental problems including learning disabilities and cognitive impairment

Question 3

Features of FXS

Answer 3

Long and narrow face
Large ears 
Prominent jaw and forehead 
Flat feet
Macroorchidism

Question 4

FXS is diagnosed by

Answer 4

Blood test

Question 5

Molecular basis of FXS

Answer 5

CGG trinucleotide expansion repeats at gene locus Xq27.3 causing alteration in FMR1 gene

Question 6

Normal/ healthy CGG trinucleotide expansion repeat

Answer 6

6-55

mRNA produces FMRP

Question 7

Premutation CGG trinucleotide expansion repeat

Answer 7

55-200

May show mild cognitive and motor deficits in old age

Question 8

Abnormal CGG trinucleotide expansion repeat

Answer 8

Full mutation over 200-1000 repeats
No mRNA, no protein
Shown in western blot

Question 9

Evidence of FXS

Answer 9

Use drosophila model

Question 10

Advantage to drosophila model

Answer 10

No licence required and short generation time

Question 11

Drosophila gene used..

Answer 11

dFMR1 which is the orthologue of FMR1

Question 12

Study social interaction of drosophila (impaired in ASD)

Answer 12

Courtship

Forward to female and tapping, vibrating and copulation

Question 13

Dockendorff et al 2002

Answer 13

Looked at WT and mutant flies with mutation in dFMR1 gene

Question 14

Dockendorff et al 2002 courtship assay

Answer 14

10 min assay with virgin female and 5 day old male mutant

Question 15

Dockendorff et al 2002
courtship assay
RESULTS

Answer 15

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

Question 16

Conclusion of Dockendorff et al 2002 assay

Answer 16

Less social interaction of the mutants

Question 17

Advantages to Dockendorff et al 2002 assay

Answer 17

Cheap to keep, quick generation interval, brain autopsy

Question 18

Disadvantages to Dockendorff et al 2002 assay

Answer 18

Too different from humans

Sequence identity between FMR1 and dFMR1 is low

Question 19

Tuberous sclerosis complex is..

Answer 19

associated with ASD
Causes mainly benign tumours to develop in different parts of the body
Behavioural problems such as ASD

Question 20

TSc ranges from mild to severe

Answer 20

Autosomal dominant rare genetic disease that affects

1 in 6000 people

Question 21

Prevalence of ASD in TSC patients

Vignoli et al 2015

Answer 21

High prevalence

40%

Question 22

Symptoms of TSC

Answer 22

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

Question 23

Molecular basis of TSC

Answer 23

Single gene mutation in TSC1 (hamartin) or TSC2 (tuberin)

Usually tumour suppressors regulating mammalian target of rapamycin (mTOR) signalling pathway

Question 24

Mutations of TSC1 and 2 cause..

Answer 24

Hyperactivation of the pathway causing abnormal cell growth, proliferation and tumourgenesis
Uncontrolled pathway

Question 25

Link of TSC to ASD demonstrated by

Answer 25

Jeste et al 2014

Question 26

Jeste et al TSC study

Answer 26

40 infants with TSC included Autism observation scale at 6, 9, 12 and 18 months Diagnostic observation schedule at 18, 24 and 36 months

Question 27

Jeste et al 2014 results

Answer 27

55% diagnosed with ASD

Question 28

Usefulness of AOSI as a measure of ASD behaviour evaluated by Capal et al 2017

Answer 28

Found it useful clinical tool in determining which infants with TSC are at increased risk for developing ASD

Question 29

Activity Dependent Neuroprotective Protein syndrome

Answer 29

Complex neurodevelopmental disorder that affects the brain and many other areas and functions of the body

Question 30

ADNP syndrome patients have

Answer 30

Mild to severe delays in intelligence, speech and global motor planning Causes behaviour disorders e.g. ASD

Question 31

Molecular basis of ADNP syndrome

Answer 31

Caused by de-novo ADNP brain gene (locus 20q13.13) mutation found by Helsmoortel et al in 2014

Question 32

ADNP is

Answer 32

Vasoactive intestinal peptide responsive gene

Question 33

ADNP gene normally..

Answer 33

Important in brain function and development as well as protecting nerve cells against electrical blockage

Question 34

Aetiology of ADNP

Answer 34

Uncertain but thought that abnormal gene product competes with WT to bind to BAF(?) complexes

Question 35

Arnett et al 2018

Answer 35

Examined the ASD phenotype in sample of representative youth with ADNP disruption

Question 36

Arnett et al 2018 found..

Answer 36

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