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Northwestern University Feinberg School of Medicine
Center for Autism and Neurodevelopment

FMR1

The FMR1 (Fragile X Mental Retardation 1) gene is critical for normal brain development and function, as it provides instructions for making the FMRP (Fragile X Mental Retardation Protein). FMRP regulates protein production, which is vital for healthy brain development and synaptic function (the connections between brain cells). Mutations in this gene can disrupt these processes, leading to a range of neurodevelopmental and neurodegenerative symptoms known as FMR1-related disorders.

 Biological Function

  • FMRP is primarily found in the brain, where it plays a key role in synaptic plasticity, which is essential for learning and memory.
  • FMRP is expressed ubiquitously from early development through adulthood, though most concentrated in the brain and spermatogonia.
  • FMRP also has a role in female reproductive function.
  • FMRP acts as a selective RNA-binding protein that inhibits the translation of numerous RNA targets, many of which are involved in synaptic plasticity. A lack of FMRP leads to excess protein synthesis.

 Mutations

Types of FMR1 Mutations and Associated Conditions:

Mutations in the FMR1 gene are primarily characterized by the number of CGG trinucleotide repeats in a specific region of the gene.

  1. Normal FMR1 Gene: Typically has 29–34 CGG repeats.
  2. Premutation (55–200 CGG repeats):
    • Individuals with a premutation generally do not develop Fragile X Syndrome (FXS) but can experience other health issues.
    • The gene is still transcribed and translated, but FMRP synthesis may be normal or slightly reduced.
    • Premutations can expand to a full mutation in future generations.

    Associated Conditions:

    • Associated Condition: Fragile X-associated Tremor/Ataxia Syndrome (FXTAS): A late-onset neurodegenerative disorder (more common in males over 50) causing intention tremor, balance problems (ataxia), memory issues, and Parkinsonian features.
    • Associated Condition: Fragile X-associated Primary Ovarian Insufficiency (FXPOI): Affects some women with a premutation, leading to reduced ovarian function and early menopause before age 40.
    • Associated Condition: Fragile X-associated Neuropsychiatric Disorders (FXAND): An umbrella term for neuropsychiatric and physical conditions observed more frequently in premutation carriers, including anxiety, depression, autistic-like traits, and chronic pain.
  3. Full Mutation (>200 CGG repeats):
    • This is typically a "dynamic mutation" where the CGG repeats expand significantly.
    • The expanded repeats lead to methylation of the gene, which effectively "switches off" the FMR1 gene, preventing the production of FMRP.

    Associated Condition: Fragile X Syndrome (FXS): The most common inherited cause of intellectual disability. Symptoms are usually more pronounced in males and can include:

    • Intellectual and Developmental Disabilities: Ranging from mild learning disabilities (more common in females) to moderate-to-severe intellectual disability (more common in males), developmental delays (motor, speech), and speech and language delays.
    • Behavioral and Emotional Challenges: ADHD symptoms, anxiety, features of Autism Spectrum Disorder (ASD), hand flapping, irritability, and shyness.
    • Physical Features: Can become more apparent with age, especially in males, and may include a long face, large ears, prominent jaw and forehead, unusually flexible fingers, flat feet, and enlarged testicles (macroorchidism) in males after puberty.
    • Other Potential Issues: Sensory sensitivities, ear infections, seizures, and sleep disorders.
  4. Point Mutations or Deletions: Account for a small percentage (1–2%) of FXS cases.
  5. Intermediate (Grey Zone) Alleles (45–54 CGG repeats): Generally considered stable and not associated with clinical symptoms or a high risk of expanding to a full mutation.

 Incidence

• Full Mutation (FXS): Approximately 1 in 4,000-7,000 males and 1 in 6,000-11,000 females.
• Premutation Carriers: Approximately 1 in 150-250 women and 1 in 400-850 men.
• Intermediate Alleles: Approximately 2~3 in 100 individuals.

 Associated Conditions

FMR1 gene mutations are linked to several distinct clinical conditions, depending on the size and nature of the mutation:

  • Fragile X Syndrome (FXS):
    The most well-known FMR1-related condition, caused by a full mutation (>200 CGG repeats) that silences the FMR1 gene. It leads to intellectual disability, developmental delays, behavioral challenges, and physical features more commonly seen in males.

  • Fragile X-associated Tremor/Ataxia Syndrome (FXTAS):
    A late-onset neurodegenerative disorder primarily affecting male premutation carriers over age 50. Symptoms include tremors, balance issues (ataxia), memory loss, and Parkinson-like features.

  • Fragile X-associated Primary Ovarian Insufficiency (FXPOI):
    Affects some female premutation carriers, causing reduced ovarian function, irregular periods, infertility, and early menopause (before age 40).

  • Fragile X-associated Neuropsychiatric Disorders (FXAND):
    An umbrella term for various mental health and neurological symptoms seen more frequently in premutation carriers. These may include anxiety, depression, ADHD, autistic traits, and chronic pain.

 Symptoms

Symptoms commonly seen in individuals affected by FMR1-related conditions include:

  • Cognitive and Developmental Delays: These can range from mild learning challenges to moderate or severe intellectual disability. Delays in motor, speech, and language development are also common.

  • Behavioral and Emotional Characteristics: Many individuals exhibit symptoms of ADHD, anxiety, social avoidance, irritability, hand flapping, and traits associated with Autism Spectrum Disorder (ASD).

  • Physical Features: Some may have distinctive physical traits such as a long face, large ears, prominent forehead or jaw, flat feet, unusually flexible fingers, and—particularly in males after puberty—enlarged testicles (macroorchidism).

  • Other Common Issues: Sensory sensitivities (e.g., to sound or touch), frequent ear infections, seizures, and sleep disturbances are also frequently reported.

 Research at Northwestern

 Genetic Testing

  • FMR1 disorders are inherited in an X-linked manner, meaning the gene is on the X chromosome.
  • Males (one X chromosome) are more likely to be affected if they inherit a mutated gene.
  • Females (two X chromosomes) can be carriers and may or may not develop symptoms.

 Clinical Trials

Several clinical trials are currently underway to explore new treatments for Fragile X-related conditions. These efforts focus on improving cognitive function, managing behavioral symptoms, and addressing underlying biological mechanisms.

  • Zatolmilast (BPN14770) is being studied for its ability to enhance cognitive function in individuals with Fragile X Syndrome. This therapy targets a specific enzyme (PDE4D) to help improve learning and memory. To learn more, follow this link: https://clinicaltrials.gov/study/NCT05163808

  • SPG601, a BK channel activator, is in development to address synaptic dysfunction, a core issue in FXS. Early trials show promising effects on brain signaling and cognitive performance. To learn more, follow this link: https://clinicaltrials.gov/study/NCT06413537

  • ZYN002 (a topical cannabidiol gel) is being tested for its potential to reduce anxiety, irritability, and social withdrawal in children and adolescents with Fragile X Syndrome. To learn more, follow this link: https://clinicaltrials.gov/study/NCT03614663

  • LYT-300, an oral form of allopregnanolone, is being explored for individuals with Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). This compound may help manage motor and cognitive symptoms in older adults. To learn more, follow this link: https://clinicaltrials.gov/search?cond=FXTAS&viewType=Table

  • For Fragile X-associated Primary Ovarian Insufficiency (FXPOI), research is focused on understanding reproductive decline and exploring fertility preservation options. Studies aim to uncover why some carriers are more affected than others. To learn more, follow this link: https://www.nichd.nih.gov/health/topics/fxpoi/findastudy

 Patient advocacy organizations

These organizations provide vital resources, support, and advocacy for individuals and families affected by FMR1-related conditions:

  • National Fragile X Foundation (NFXF)
    Offers education, community support, advocacy efforts, and promotes research for Fragile X-associated disorders.
    To learn more, visit: https://fragilex.org

  • FRAXA Research Foundation
    Focused on funding scientific research aimed at finding effective treatments and ultimately a cure for Fragile X Syndrome.
    To learn more, visit: https://fraxa.org

  • Fragile X Clinical & Research Consortium (FXCRC)
    A coordinated network of clinics offering comprehensive care and contributing to research across the Fragile X community.
    To learn more, visit: https://fragilex.org

  • University-Based Centers
    Several academic institutions provide clinical care and research programs for FMR1-related conditions, including:
    - UC Davis MIND Institute
    - Waisman Center at the University of Wisconsin–Madison
    - Kennedy Krieger Institute at Johns Hopkins University

  • National Institutes of Health (NIH)
    The NIH funds and supports a wide range of research projects to better understand and treat FMR1-related disorders.
    To learn more, visit: https://www.nih.gov

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