Mechanisms of Neurodevelopmental Disorders

Question 1

What are two broad risk factors for NDD?

Answer 1

Genetic
Environmental (maternal use of substance, low socioeconomic status, preterm birth, etc.)

Question 2

Define the following types of genetic alleles

Hypomorphic
Haploinsufficient
Antimorphic
Hypermorphic
Neomorphic

Answer 2

Hypomorphic: gene has reduced activity
Haploinsufficient: single copy of the wild- type allele is insufficient to produce the standard phenotype
Antimorphic: acts antagonistically to the wild-type allele
Hypermorphic: increase in normal gene function
Neomorphic: gene with a novel molecular function

Question 3

What are the four genetic mechanisms of ASD?

Answer 3

Autosomal recessive
Autosomal dominant
X-linked
Additive risk
Copy number variation

Question 4

True or false: if having an autosomal dominant of ASD, you might not know.

Answer 4

True: mutations could not affect the brain cells.

Question 5

List 3 characteristics of Rett syndrome.

Answer 5

Regression: loss of social interactions and language
Progression: stereotypic behaviours, e.g. hand-wringing
Mild neuropathological findings

Question 6

Rett syndrome is most often sporadic or inherited?

Answer 6

Sporadic (de novo)

Question 7

What causes Rett syndrome? How was it discovered it it is often a syndrome caused de novo?

Answer 7

studying the rare familial cases (on the left) led to the discovery of disease causing gene MECP2 on X chromosome

Question 8

Why do mutations in MECP2 gene that affects its c terminal have less severe conseq.?

Answer 8

Because functional domains are preserved

Question 9

Does a MeCP2 duplication have similar effects in males and females?

Answer 9

No, sexually dimorphic

Question 10

Neurobiologically, what does MeCP2 regulate?

Answer 10

glutamatergic synaptic numbers and synaptic strength

Question 11

What does MECP2 code for?

Answer 11

A transcriptional regulator

Question 12

Does MECP2 upregulate or downregulate gene expression? On what does it depend?

Answer 12

Both, depends on the complex it recruits:
CREB = activator
NCoR-HDAC3 complex = repressor

Question 13

How was it researched whether MeCP2 caused duplication syndrome by functioning as an antimorphic or hypermorphic allele?

Answer 13

Use of KO and Tg mice

If antimorphic: MeCP2 KO and Tg show similar molecular changes (because too much or too little MeCP2 disrupts important protein complex)

If hypermorphic: MeCP2 KO and Tg show inverse molecular changes (MeCP2 KO-> loss of MeCP2 function, MeCP2 Tg-> too much MeCP2 function)

Question 14

What happens when MECP2 is overexpressed or underexpressed at the circuit level?

Answer 14

Loss of MECP2 = decreased synaptic strength
Increase of MECP2 = increased synaptic strength

^^ these are the neurobiological consequences aforementionned

HOWEVER, at the circuit level, gain OR loss BOTH drive hypersynchrony (risk for seizure)