Overview of Fragile X Syndrome

Introduction

• Genetic disorder causing intellectual disability, behavioral and learning challenges.
• Named due to the fragile end of the X chromosome visible under a microscope.

Epidemiology

• Prevalence:
  • 1 in 4,000 males
  • 1 in 7,000 females
• Most common inherited cause of intellectual impairment after Down syndrome.

Genetic Basis

• Caused by mutation in the FMR1 gene on the X chromosome.
• Leads to lack of production of the fragile X mental retardation protein (FMRP).
• FMRP is crucial for normal brain activity; its absence leads to mental retardation and social issues.
• X-linked genetic disorder: males (one X chromosome) are more affected.

Physical Characteristics

• Distinct features:
  • Long face
  • Abnormally large ears
  • Prominent jaw and forehead
• Common symptoms:
  • Intellectual disability
  • Learning disabilities
  • Attention disorders
  • Hyperactivity
  • Social anxiety
  • Repetitive behaviors
  • Social withdrawal
  • Delayed speech and language development

Molecular Basis

• FMR1 gene contains multiple CGG repeats in its 5' UTR region.
• Normal: 5 to 44 CGG repeats
• Full mutation: more than 200 CGG repeats cause pathogenic conditions.
• Methylation of CGG repeats leads to heterochromatinization and gene silencing.
• Consequence: Non-functional FMRP, impacting brain development and function.

Function of FMRP

• mRNA Translation at synapses:
  • Binds to mRNAs involved in synaptic plasticity.
• **Dendritic mRNA Transport: **
  • Facilitates transport and localized translation at dendrites.
• Synaptic Structure and Dendritic Arborization:
  • Non-functional FMRP leads to abnormal dendritic structures.
• Synaptic Plasticity:
  • Regulates long-term potentiation and depression.

Neuronal Insights

• Normal Neurons: Mature synapses with mushroom spines.
• FMR1 Knockout Neurons: Immature, dysmorphic synapses.
• Role of LIMK1 and Cofilin:
  • Proper balance important for actin polymerization and dendritic formation.
  • Altered FMRP results in excessive actin polymerization.
• Overall Brain Structure:
  • Larger brain size and dilated ventricles (common but not differential).
  • Caudate nucleus in basal ganglia is enlarged.

Circuit Activity

• Excitatory/Inhibitory Balance:
  • Disrupted balance in FMRP deficiency leads to susceptibility to seizures.
• GABAergic Synapses:
  • Non-functional due to deficient FMRP, leading to excess excitatory activity.

Diagnosis

• Physical Features: Long face, large ears, prominent forehead and jaw ridge.
• Family History: Important for genetic disorders.
• Genetic Testing: Confirmatory, based on CGG repeat number.

Treatment and Management

• No cure available.
• Current Trials: Focus on GABA agonists to balance excitatory input.
• **Symptom Management: **
  • Speech and language therapy
  • Genetic counseling
  • Supportive medications (SSRIs, dopamine agonists)

Conclusion

• Informative video about Fragile X Syndrome.
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