L10: Neurodevelopmental Disorders

Question 1

What factors determine the precise neurodevelopmental pathway?

Answer 1

1. Environmental influences

2. Random developmental fluctuation

Question 2

What process occurs at 10-20 weeks of neurodevelopment?

Answer 2

Neurons are born in the ventricular zone (VZ) and migrate along radial glia to take more superficial positions in the cortex in an inside out arrangement- later neurons are more superficial than older ones.

Question 3

What are the failure types of neurodevelopment?

Answer 3

Failure in:
Cortical organisation
Neuronal proliferation
Neuronal migration
Neuronal connectivity.

Question 4

Can you give examples of each type of neurodevelopmental failure?

Answer 4

Cortical organisation: Polymicrogyria (excess gyrae) Mutations in ARX and TUBB2B

Proliferation: Focal cortical dysplasia. (disruption of mTOR, overgrowth of neurons)

Migration: Lissencephaly (DCX gene, X linked. Severely affects males, wmen get banded heterotopia)

Periventricular nodular heterotopia: FLN mutation, neurons in VZ cant migrate out- grey matter around the VZ.

Connectivity: Schizophrenia, Autism, intellectual disability, ADHD, Epilepsy. F

Question 5

What are 3 causes of epilepsy?

Answer 5

1. Mendelian inheritance
2. Additive inheritance (common variant common disease)
3. Rare variant common disease.

Question 6

Explain the CVC disease and RVC disease hypotheses.

Answer 6

CVC: Mutations confer small risk, but they are very common in the population so overall confer a high attributable risk of a disease.

RVC: Rare mutation, but the effect is large.

Question 7

What are the root causes of mendelian epilepsies?

Answer 7

Ion channel subunit genes

Non ion channel genes (
LGI1- lateral temporal lobe
GLUT1-absence and generalised DEPDC5- Variable foci (frontal,temporal)

Question 8

Which loci were identified in the largest GWAS epilepsy study to date?

Answer 8

SCN1A: Most important gene,- Voltage gated sodium channel

PCDH7: All epilepsies

VRK2/FANCL- associated with GGE

Question 9

Why might 2 epilepsy patients with a mutation in the same gene not respond to the same treatment?

Answer 9

Mutations in the same gene can lead to different phenotypes and different responses to treatments. Pharmacological response cannot be modelled in vitro.

Question 10

Which domains is human intelligence broken into?

Answer 10

1: Reasoning
2: Speed
3: Memory
4: Reading.

1-3=fluid (peak at 30)
4= crystalized (we learn and develop)

Question 11

What was performed to investigate pathways of intelligence?

Answer 11

Gene network analysis.

Took gene expression from 122 epilepsy patients. Network analysis performed. Coregulatory network built based on genes coregulation.

Question 12

Which modules identified were of interest and what is their function?

Answer 12

M1: Enriched in synaptic regulation genes.

M3: Post synaptic density genes.

M11: Microtubule regulation.

M19: Ribonucleoprotein complex formation.

Question 13

Which domains were M1 and M3 involved in?

Answer 13

M1: Crystalized
M3: Cognitive fluid ability.

Question 14

M3 was associated with which neurodevelopmental disorders?

Answer 14

Epileptic encephalopathy
Intellectual disability
And other (schiz, autism?)

Therefore genes that underpin intelligence can also correlate to neurodevelopmental disease when altered.