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Fragile X Syndrome

What is Fragile X syndrome?

Two boys smiling at Special OlympicsFragile X syndrome (FXS) is the most common form of inherited intellectual and developmental disability and autism spectrum disorder (ASD). In addition to developmental challenges and features of ASD, patients often have behavioral challenges and characteristic physical features such as a long face and enlarged ears.

Fragile X syndrome affects an estimated 1 in 4,000-7,000 males and approximately 1 in 6,000-11,000 females. Because fewer than 200,000 cases of FXS are diagnosed in the U.S. each year, it is classified as a rare disease.

FXS is caused by a change in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene on the X chromosome. The FMR1 gene is essential for normal neural development.

A significantly higher number of males are affected by Fragile X syndrome because males have a single X chromosome and only one copy of the FMR1 gene. In females, the effects are often less severe because they have a second X chromosome with a second FMR1 gene. Females who carry one copy of an altered FMR1 gene have a 50% chance of passing that variant to each of their children. Males with an FMR1 variant will pass it on to all of their daughters but not to their sons.

Symptoms of FXS may appear before 12 months. On average, males with FXS are diagnosed around three years of age. Females are typically diagnosed a little later, at approximately 42 months old, and because of the milder features, some females go undiagnosed.

Characteristics of Fragile X Syndrome:

  • Intellectual Disability: Ranges from mild to severe
    • The majority of males with Fragile X syndrome demonstrate moderate intellectual disability with an average IQ under 55
    • Among females with a diagnosis of Fragile X syndrome, approximately 25% have an intellectual disability, and another 25% have an IQ in the borderline range (70-85).
    • Speech and language are typically delayed
    • Individuals with Fragile X syndrome also typically have delayed motor skills, such as walking, talking, or going to the bathroom on their own
  • Behavioral and Emotional Challenges:
    • Anxiety
    • Hyperactivity
    • Attention deficit
    • Impulsivity
    • Poor eye contact
    • Hand flapping
    • Autism spectrum disorder
  • Physical Features: 
    • Long face
    • Large ears
    • Flat feet
    • Hyper-flexible joints
    • In males, enlarged testicles following puberty
  • Speech and Language Delays: FXS typically causes difficulty with communication and social interactions.
  • Sensory Sensitivities: Overreactions to sensory stimuli, such as sounds and textures
  • Medical Issues: Individuals with FXS are more susceptible to several medical conditions including:
    • Ear infections (typically because of poor connective tissue)
    • Seizures
    • Crossed eyes
  • Other characteristics that are common among individuals with Fragile X:
    • Sociable and friendly
    • Strong visual and long-term memory
    • A positive sense of humor

Testing for Fragile X Syndrome

Before 1991, a chromosome test was the only laboratory method to diagnose Fragile X syndrome, and that test missed many cases, especially those in females. In 1991, once the FMR1 gene was discovered as the cause of FXS, more accurate testing became available.

The change in the FMR1 gene that causes FXS involves the expansion of part of the DNA sequence where three letters of the DNA code are repeated. In FXS, this three-letter repeat is CGG. The typical number of CGG repeats for someone without FXS is <55. Individuals with 55-200 repeats have a premutation. Those with a premutation are not affected with FXS, but may have other associated concerns and may pass the mutation on to their children. Those with >200 CGG repeats have a full mutation which causes FXS.

A healthcare provider can order a DNA test on a blood sample or saliva swab to determine how many CGG repeats are present in the FMR1 gene.

There are three general circumstances in which Fragile X testing should be considered:

  • If there are clinical symptoms that suggest Fragile X syndrome, Fragile X-associated tremor/ataxia syndrome (FXTAS), or Fragile X-associated primary ovarian insufficiency (FXPOI).
  • If there is a family history of FXS or FXTAS, or autism of unknown cause
  • Family history of Fragile X syndrome

Fragile X and Greenwood Genetic Center (GGC)

The Greenwood Genetic Center (GGC) (www.ggc.org) has studied Fragile X syndrome since the mid-1980s. Once the gene was identified in 1991, GGC became one of the first labs in the US to offer this testing clinically. GGC continues to be heavily involved in Fragile X research as part of the National Fragile X Clinical and Research Consortium (FXCRC), funded by the National Fragile X Foundation and the US Centers for Disease Control and Prevention.

GGC operates a Fragile X syndrome clinic under the direction of Carrie Buchanan, MD, which serves both pediatric and adult patients with FXS and Fragile X Premutation-Associated Conditions (FXPAC), including Fragile X-Associated Neuropsychiatric Disorders (FXAND). GGC’s FXS Clinic provides consultations with a developmental-behavioral pediatrician and a genetic counselor. The clinic also assists with referrals to medical specialists, including behavioral and therapy services. Genetic testing is also available through GGC’s Molecular Diagnostic Laboratory.

Sam Blackwood was diagnosed with FXS by GGC when he was almost 2 years old after missing key developmental milestones. GGC has provided significant support to the Blackwell family, helping them navigate through state and educational support programs in South Carolina. Sam continues to be followed in the Center’s FXS clinic where he has participated in research projects and clinical trials.

FXS Research at GGC

GGC’s FXS Clinic is participating in several clinical programs assessing potential therapeutics for Fragile X Syndrome. GGC is one of 25 clinical sites for RECONNECT, a randomized, double-blind, placebo-controlled, multiple-center study, to assess the efficacy and safety of ZYN002, a pharmaceutically manufactured cannabidiol, formulated as a clear gel that can be applied to the skin, in children and adolescents with FXS. This is an 18-week trial currently enrolling children aged three through 29 years.

GGC is also one of 15 clinical sites supporting a randomized, double-blind, placebo-controlled, multi-center study, to assess the efficacy and safety of BPN14770, a phosphodiesterase inhibitor, in male adolescents (aged 9 to 45years) with FXS. This is a 13-week trial.

The clinic is also a site supporting the CDC-funded FORWARD-MARCH (Fragile X Online Registry With Accessible Research Database Multiple Assessments for Research Characterization) study. FORWARD-MARCH is a multisite observational natural history study affiliated with the FXCRC using multiple assessments to characterize behavioral, adaptive, and cognitive functions to further improve understanding of the natural history of FXS. It also acts as a research hub to connect patients to current projects.

Additionally, GGC is one of three sites assessing the relationship between hypermobility-related disorders and Fragile X premutation status. GGC is currently enrolling women with a Fragile X premutation in this single-visit, observational study.

Other FXS-Related Issues

In addition to FXS, there are other conditions related to variants in the FMR1 gene on the X chromosome. These typically affect older individuals who have a premutation of the FMR1 gene.

  • Fragile X-associated Tremor/Ataxia Syndrome (FXTAS): FXTAS is caused by a premutation of the FMR1 gene of 55 to 200 CGG repeats. This does not silence the gene but leads to elevated levels of FMR1 mRNA, which can cause cellular problems.
    • Symptoms: Progressive neurological symptoms, including tremors, ataxia (loss of coordination), memory problems, and cognitive decline.
    • Age of Onset: Typically affects older adults, usually males over the age of 50
  • Fragile X-associated Primary Ovarian Insufficiency (FXPOI): FXPOI is characterized by reduced function of the ovaries. The FMR1 gene produces the protein FMRP, which is important in normal ovarian function. FXPOI is one of the most common genetic causes of ovarian failure.
    • Symptoms: Reduced fertility, infertility, unpredictable menstrual cycles, premature menopause
    • Age of Onset: FXPOI typically affects women under the age of 40 who have the premutation in the FMR1 gene