Fragile X Syndrome (FXS) Lecture Notes

A set of flashcards covering key concepts and definitions related to Fragile X Syndrome (FXS) for exam preparation.

Fragile X Syndrome (FXS)

A leading cause of inherited intellectual disability.

Epidemiology of FXS

Approximately 1:4,000 in males and 1:6,000 to 1:8,000 in females.

FMR1 gene

Gene located on the X chromosome responsible for FXS, mutations affect FMRP production.

CGG repeat expansion

A trinucleotide repeat expansion in the FMR1 gene that leads to FXS when it exceeds 200 repeats.

FMRP (Fragile X Mental Retardation Protein)

An mRNA binding protein that suppresses protein translation.

Clinical description of FXS

Includes traits such as intellectual disability, anxiety, depression, and specific craniofacial abnormalities.

Sex difference in FXS severity

Males often exhibit moderate to severe intellectual disability, whereas females display milder symptoms.

Diagnostic methods for FXS

Typically diagnosed through genetic testing for mutations in the FMR1 gene.

Role of mGluR5 in FXS

Increased mGluR activity leads to excessive protein synthesis, contributing to symptoms of FXS.

Biomarkers associated with FXS

Potential indicators include levels of specific miRNAs, cytokines, and GABA subunits.

Therapeutic approaches for FXS

No cure exists; therapies focus on managing symptoms through educational interventions and pharmacological treatments.

Animal models of FXS

Fmr1 knockout mice exhibit impaired intellectual function, abnormal spine development, and social behavior deficits.

mGluR theory of FXS

The theory that increased mGluR signaling leads to excessive translation, opposing FMRP's normal function.

Clinical description

• Intellectual Disability:

- IQ is usually 30-50.

- Learning disability

- Delayed social, emotional, and language development

• Mental problems:

- Anxiety

- Depression

- Obsessive compulsive behavior

• Craniofacial abnormalities

- Large head, long face, prominent forehead and chin, protruding ears

• Seizures

• Large testes after puberty

• Behavioral changes:

- ASD and/or ADHD is common.

- Poor eye contact

- Flapping or biting of hands

Two requirements for FMR1 gene alteration

. Trinucleotide repeat expansion:

. Aberrant methylation

Loss of FMRP:

• Immature dendritic spines

• Higher density of immature

dendritic spines

• Loss of synaptic refinement or

“pruning”

FMRP and GABA

The levels of GABA receptors are

decreased in the absence of FMRP.

Reduced GABA signaling results in

impulsivity due to the excitation/inhibition Therapeutic approachesimbalance

Therapeutic approaches

No treatment is available to cure FXS.

Why are the frequency and severity of Fragile X Syndrome lower in females?

Females have two X chromosomes, so they are likely to have one normal allele that can compensate for the mutated allele, reducing the severity of symptoms.

MPEP, fenobam, or AFQ056 have been considered for FXS treatment. These drugs are

known to block mGluR5. Why does mGluR5 inhibition thought to be beneficial for FXS?

It is believed that mGluR5 inhibition can reduce excessive signaling pathways that contribute to the symptoms of Fragile X Syndrome, thus restoring proper synaptic function and improving behavioral outcomes.

What mRNAs do FMRP regulate?

FMRP regulates mRNAs involved in synaptic function and plasticity, including those related to dendritic development and neuronal signaling.

Synaptic structure and function:

- ARC

- CAMKII

- MAP1B

- PAK (p21-activated kinase)

- GSK-3

- APP

These proteins are crucial for synaptic plasticity, signaling, and the development and maintenance of synaptic structures in the brain.