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Flashcards in Rett Syndrome Deck (16)
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1
Q

What is the incidence of Rett Syndrome?

A

1/10,000 female births

2
Q

What are the clinical features?

A

Normal early postnatal development.
Rate of head growth abnormally low.
Developmental regression at 9-18 months
- loss of skills (hand, speech, locomotion)
- social withdrawal
- onset of hand stereotypies (hand wringing
- breathing/autonomic dysfunction, disturbed mood and sleep patterns.

After regression at about 4+ years there is a plateau
Slow progress thereafter
Social skills limited.
Need full care
Later - seizure onset, scoliosis
Can live to >50 years old, but sudden early death in 25%

3
Q

What are the clinical features in male hemizygotes?

A

Severe encephalopathy

Fatal soon after birth or earlier.

4
Q

What is the inheritance pattern for Rett Syndrome?

A

X-linked dominant.

5
Q

Which gene is affected?

A

MECP2 gene - encodes methyl CpG binding protein 2

6
Q

Is it a loss of function or gain of function mutation?

A

Loss of function.

7
Q

What is the function of MeCP2?

A

Epigenetic modification of cytosine
Associated with compact chromatin structure and reduced capacity for expression - role in suppressing transcription.
Binds methylated CpG and keeps those genes turned of.

8
Q

What explains the variance in severity?

A

Skewed X inactivation and the type of MECP2 mutation.

9
Q

What is the phenotype in the MECP2 knockout mice?

A
Brain weight and size reduced.
 - mainly frontal/temporal cortical layers affected.
 - brainstem also affected
Cortical thickness reduced
No cell loss
Neuronal cell packing density increased
 - mainly associated with reduction in 'bushiness' of dendritic arborisation
Cortical layering nearly normal.
10
Q

What happens to the neurons in KO mice?

A

All neurons reduced in size.

11
Q

What is the evidence that RTT is the result of failure of neurons to mature in their function?

A

Huge postnatal increase in MECP2 expression, coincides with maturation of neurons.

12
Q

How might research develop to treat RETT.

A

Reactivation of Mecp2 in reversible-KO mice after symptom onset could reverse and improve the condition - gene rescue.

13
Q

Have you read the review?

A

Gadalla et al. review, Biochm. J. 2011

14
Q

Could RTT be treated with gene therapy, what would be required of a vector system?

A

Must transduce non-dividing cells (neurons)
Must efficiently enter the CNS and reach and transduce enough neurons.
Must lead to stable long-term transgene expression at near WT level in transduced cells.
Must not overexpress above a certain threshold.
Must not provoke a serious immune response.

15
Q

How would the outcome of gene therapy be measured?

A

Distribution of transduced cells, cell types, MeCP2 expression level in both ‘null’ and ‘WT’.
Ability to prevent/rescue molecular phenotype - nuclear size, neuronal soma size, mature neuronal marker expression level, dendritic patterning and growth.
Ability to prevent/rescue the phsyiological phenotype - neuronal connectivity, synaptic function and regulation, network behaviour.
Ability to prevent/rescue the whole organism phenotype - body growth size, brain size, behavioural/breathing deficits.

16
Q

Have gene therapies been tested in animal models?

A

Yes, mouse model using adeno-associated virus vector.
Survival, severity and bodyweight all improved in male KO mice given AAV/Mecp2 vector.
Neuronal nuclear size became normal in cells transduced with AAV/Mecp2 vector.