Fragile X

Question 1

Why does fragile X effect men and women differently?

Answer 1

X-linked therefore impacts women less as if there is only one faulty copy of gene then other X chromosome makes up for it.

Question 2

What gene is impacted in fragile X syndrome and how?

Answer 2

Tandem CGG repeats (above 55) in the promoter region of FMR1

Question 3

What are the 4 types of fragile X?

Answer 3

Full mutation (FXS)
FXTAS (Pre fragile x-associated tremor/ataxia syndrome)
FXPOI (Pre fragile x-associated primary ovarian insufficiency
FXAND (Pre fragile x-associated neuropsychiatric disorder)

*full mutation must have +200 repeats whereas pre above 55 (Hagerman, 2017)

Question 4

How do moscaic cases of fragile x occur and how do they differ?

Answer 4

Some cells have full mutation 200+ CGG repeats whereas other cells only have 55+.

Mosaic cases are often less severe behavioural and cognitive defects than Full.

Question 5

There has been recent reporting of individuals with deletion or point mutation in FMR1. How do these individuals relate to FXS?

Answer 5

Symptoms of FXS in some cases. In FXS (full) the tandem repeats lead to silencing of the gene. Deletion and point mutation similar to this.

Question 6

In FXS what causes silencing of FMR1 and why?

Answer 6

The tandem repeats cause transcriptional silencing (Kumari, 2019).

Theshold is not well understood however silencing occurs ~11 weeks gestation and is thought to be related to h3 dimethylation marking.

Question 7

How is FMR1 impacted in pre-mutation versions of fragile x?

Answer 7

Excessive transcription of FMR1.

Question 8

What does FMR1 stand for and do?

Answer 8

Encodes FMRP: Fragile X mental retardation protein.

Central role in gene expression, regulates translation of hundreds of mRNAs involved in development and maintenance of synaptic connections esp metabotropic glutamate receptor.
This is reason also known as synaptic functional regulator FMR1.

Question 9

Where is FMR1 found?

Answer 9

Ubiquitous but highest concentration in brain and testicles.

Question 10

How many people develop fragile X?

Answer 10

1/4000 males
1/8000 females

Question 11

Outline FXTAS

Answer 11

Movement disorder also associated with loss of cognition. Develops in 60s

40% male carriers and 16% female will develop.

80% of FXTAS have peripheral neuropathy which presents earlier than motor symptoms. Numbness and neuropathic pain is typical. Study of 16 patients found reduction in sensory nerve amplitude (Cabal-Herrera et al., 2020)

Question 12

Outline FXPOI

Answer 12

20% of female carriers will develop.

Early menopause (5 years earlier), irregular menstrual cycles and subfertility. (Fink et al., 2018)

Question 13

Outline FXAND

Answer 13

Unlike other pre seen early. Psychiatric probls occur before neurological.

Study of 35 (5-23yrs) pre against controls found that 70% met criteria for anxiety compared to 22.6% controls.

control is much higher than general pop at 9.8% for age range.

Question 14

Outline symptoms of full fragile X

Answer 14

Intellectual disability:

baby: motor delays, seizures, hyperactivity, language delay.

Childhood: autism, aggression

Adulthood: anxiety, poor attention, cognitive decline.

Question 15

What heart condition is FXS associated with and how might this contribute to symptoms?

Answer 15

Mitral valve prolapse: floppy valve doesn’t close properly so impaired transport of blood.

Leads to anxiety

Question 16

Outline studies of FXS and ASD

Answer 16

Hall et al., 2010: 35.1% young males with FXS scored within autistic range.

Niu et al., 2017: cooccurring ASD results in more severe behavioural issues but less impaired social and communication.

Question 17

Outline animal model used to study FXS

Answer 17

FMRP KO mice: mild cognitive defect, hyperactivity, macroorchidism, increased sensitivity to auditory stimuli which leads to epileptic seizures.

KO mice have immature dendritic spines. Unlike humans have decreased anxiety when assessed with open field test.

Treatment via amelioration of dendritic spines to minimalise symptoms using p21 activated kinase PAK (Dolan et al., 2013)

Also mmp9, mGluR and GABA

Question 18

How is MMP9 mRNA deregulated?

Answer 18

Increased protein translation: important for dendritic spine maturation. When levels lowered to normal in mice spines mature, decreased anxiety, increased cognition.

Question 19

How is plasticity altered?

Answer 19

mGluRI - dependent LTD is increased in hippo and cerebellum of KO mice by promoting AMPAR internalisation. When AMPAR blocked several phenotypes of KO are corrected.

Potential for therapeutical uses of antagonists. And when translators of inhib used phenotypes rescued.

*most pop view that FMRP exerts control via translation.

Question 20

Outline how GABA signalling is impacted.

Answer 20

Decreased: reduced expression of half of GABA A receptor subunits, roughly 50%.

Possible pharmacological treatment with GABAA agonists (VAn de A and Koov, 2020).

Question 21

Diagnosis

Answer 21

Blood test
southern blotting detects full mutation

Question 22

Treatment of fragile X

Answer 22

Speech therapy, behavioural, SSRIs.