Lecture 17 (Fragile X)

Study Guide: Fragile X Syndrome (FXS)

Significance of Fragile X Syndrome

  • Cognitive Impairment: Most common inherited cause; significant single-gene cause of autism.

  • Prevalence:

    • Affects ~1/7,000 males and ~1/11,000 females.

    • Carrier rates: ~1/150 females and ~1/500 males.

  • Genetic Foundation: FMR1 gene; triplet repeat expansion disorder.

  • Central Nervous System Research: Insights into protein FMRP's role.

FMR1 Gene and Mutations

  • Forms of the Gene:

    • Normal: <45 CGG repeats.

    • Premutation: 55-200 CGG repeats (associated with FXTAS and FXPOI).

    • Full Mutation: >200 CGG repeats (causes FXS).

  • Inheritance and Mosaicism:

    • Premutation expands to full mutation when passed from mother to child.

    • Mosaic individuals show less severe symptoms.

Clinical Features of Fragile X Syndrome

  • Cognitive:

    • Mild to moderate impairment in males.

    • Learning disabilities and mild impairment in females.

  • Behavioral:

    • ADHD, social anxiety, and repetitive motions (e.g., hand flapping).

    • ASD behaviors in ~50% of males and ~15% of females.

  • Physical:

    • Long face, prominent ears, macrocephaly, macro-orchidism (males).

    • Joint hypermobility, flat feet.

Associated Disorders in Carriers

  • FXTAS (Fragile X-associated Tremor/Ataxia Syndrome):

    • Affects older male and female carriers; leads to tremors, ataxia, cognitive decline.

  • FXPOI (Fragile X-associated Primary Ovarian Insufficiency):

    • Menopause before age 40 in ~20% of female carriers.

Key Historical Milestones

  • 1943: Martin-Bell syndrome described.

  • 1991: FMR1 gene identified; triplet repeat amplification explained "Sherman Paradox."

  • 2020-2024: Advancements in clinical trials targeting FXP levels and neurological pathways.

Function of FMRP/FXP

  • Regulates glutamate reception and mRNA translation in neurons.

  • Impacts dendritic spine shape and density, critical for neural signaling.

Diagnosis and Treatment

  • Diagnostic Importance:

    • Early diagnosis facilitates therapy (e.g., speech, occupational, behavioral).

    • Alerts relatives about carrier risks and associated disorders.

  • Current Treatment Approaches:

    • Symptom management (e.g., ADHD medication, anxiety therapies).

    • Clinical trials on PDE4D inhibitors like BPN14770 for cognitive improvement.

    • New trial designs accounting for variability in FXP expression.

Prospects for a Cure

  • Mixed results in clinical trials for mGluR blockers.

  • Promising new trials for drugs targeting cAMP levels and FXP-related mechanisms