Fragile X Syndrome

Fragile X syndrome (FXS) is a genetic condition that causes intellectual disability, behavioral and learning challenges and various physical characteristics. Though FXS occurs in both genders, males are more frequently affected than females, and generally with greater severity. Life expectancy is not affected in people with FXS because there are usually no life-threatening health concerns associated with the condition.

2 boys outdoors wearing suits and ties

Features of Fragile X Syndrome in Males

  • Behavioral characteristics can include ADD, ADHD, autism and autistic behaviors, social anxiety, hand-biting and/or flapping, poor eye contact, sensory disorders and increased risk for aggression.
  • The majority of males with Fragile X syndrome demonstrate significant intellectual disability. Disabilities in FXS include a range from moderate learning disabilities to more severe intellectual disabilities.
  • Physical features may include large ears, long face, soft skin and large testicles (called “macroorchidism”) in post-pubertal males. Connective tissue problems may include ear infections, flat feet, high arched palate, double-jointed fingers and hyper-flexible joints.
  • No one individual will have all the features of FXS, and some features, such as a long face and macroorchidism, are more common after puberty.
  • They are also very social and friendly, have excellent imitation skills, have a strong visual memory/long term memory, like to help others, are nice, thoughtful people and have a wonderful sense of humor.
Features of FXS in Females

Features of Fragile X Syndrome in Females

  • The characteristics seen in males can also be seen in females, though females often have milder intellectual disability and a milder presentation of the syndrome’s behavioral and physical features.
  • About one-third of females with FXS have a significant intellectual disability.
  • Others may have moderate or mild learning disabilities, emotional/mental health issues, general anxiety and/or social anxiety.
  • A small percentage of females who have the full mutation of the FMR1 Gene that causes FXS will have no apparent signs of the condition—intellectual, behavioral or physical. These females are often identified only after another family member has been diagnosed.
FXS ASD Picture
FXS ASD Picture

Autism Spectrum Disorder and Fragile X Syndrome

Fragile X syndrome is the most common known single gene cause of ASD

Autism spectrum disorder (ASD) is a behavioral diagnosis. The range of symptoms in ASD vary and are generally characterized by an impaired ability to communicate and interact socially with other people. Sometimes children will not meet the diagnostic criteria for ASD but will have autistic-like features.The diagnosis of ASD is usually made by a developmental or general pediatrician, neurologist, psychologist, psychiatrist, or other specialist. A clinician may make a diagnosis of ASD after observing the behavior and language of a child and using the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for their evaluation. In addition, the diagnosis may be made after evaluating the child using a number of testing instruments, such as the Autism Diagnostic Observation Schedule – 2nd edition (ADOS-2) or the Autism Diagnostic Interview – Revised (ADI-R). These instruments are considered the gold standard – the most accurate instruments available – for a diagnosis and are often used in research.There is no blood test for ASD, and imaging studies such as MRIs don’t diagnose the condition – it is purely a behavioral diagnosis similar to Attention Deficit Hyperactivity Disorder (ADHD).

Much remains unknown about the condition—including what causes it in many individual cases. However, when a child is diagnosed with ASD, blood tests are often ordered to rule out the known genetic causes. Fragile X syndrome (FXS) is the most common known single gene cause of ASD. Other genetic causes of ASD include deletions of chromosome 15q, tuberous sclerosis and other rare genetic conditions.

Many times a child with ASD will be tested or evaluated for all the known genetic causes of autism but no cause will be found. However, family studies have shown that in families with one child with ASD there is an increased risk for another child to have the condition. This risk is not as high as in those families with an identified single gene cause, such as FXS. It is more in line with multifactorial risks, similar to heart defects or cleft lip. This leads experts to believe there is a genetic component even in those without a single gene identified cause.

Many researchers are trying to determine both the genetic and non-genetic factors that contribute to ASD.

Whereas ASD is a behavioral diagnosis, FXS is a medical, or more accurately, a genetic diagnosis. When associated with FXS, ASD is caused by the genetic change or mutation in the Fragile X gene. If a child is diagnosed with ASD and then diagnosed with FXS, he or she still has ASD, it is just that the cause of their ASD is known. It is no different than someone with FXS also having ADHD or any other behavioral symptom of FXS.

The article FXS and ASD: Similar But Different highlights a well-attended panel discussion at the 13th International Fragile X Conference that addresses the topic: FXS and ASD: Clinical Insights into the Similarities and Differences for Diagnosis and Treatment.

Many studies have evaluated the FXS-ASD link over the past decade. Since many children with FXS are interested in social interactions, they may not meet the diagnostic criteria for ASD, even though they exhibit some features of ASD such as poor eye contact, shyness, social anxiety, hand-flapping and sensory issues. Autism is much more common in boys with FXS than in girls with FXS. According to the CDC, a national parent survey found that 46 percent of males and 16 percent of females with FXS have been diagnosed or treated for ASD. The FORWARD Registry and Database tells us that 40 percent of individuals with FXS are diagnosed with ASD by their doctor in the clinics of the Fragile X Clinical and Research Consortium (FXCRC)

Studies show that individuals with FXS who have autism can have a more significant intellectual disability (lower IQ) than those with FXS who do not have autism.

For further reading on the relationship between autism and Fragile X syndrome, see:

About 10 percent of children with ASD are identified as having another genetic and chromosomal disorder, such as Fragile X syndrome. Given the possibility of a link, it is recommended that all children with ASD, both male and female, be referred for genetic evaluation and testing for FXS and any other genetic cause of ASD.

Studies show that individuals with FXS who have autism can have a more significant intellectual disability (lower IQ) than those with FXS who do not have autism.

For further reading on the relationship between autism and Fragile X syndrome, see:

  • CDC’s Fragile X-related concerns page
  • FXCRC Consensus Document titled “Autism Spectrum Disorder in Fragile X Syndrome”
  • The Fragile X Family of Disorders: A Model for Autism and Targeted Treatments:
    CGC-repeat expansion mutations of the Fragile X mental retardation 1 (FMR1) gene are the leading known cause of autism and autism spectrum disorders (ASD). Full mutation expansions (>200 CGC repeats) of the gene are generally silenced, resulting in the absence of the FMR1 protein and Fragile X syndrome. By contrast, smaller expansions in the premutation range (55-200 CGC repeats) results in excess gene activity and RNA toxicity, which is responsible for the neurodegenerative disorder, Fragile X-associated tremor/ataxia syndrome (FXTAS), and likely additional cases of developmental delay and autism. Thus, the FMR1 gene is causative of a common (autism) phenotype via two entirely different pathogenic mechanisms, RNA toxicity and gene silencing. The study of this gene and its pathogenic mechanisms therefore represents a paradigm for understanding gene-brain relationship and the means by which diverse genetic mechanisms can give rise to a common behavioral phenotype.
  • The Fragile X Syndrome–Autism Comorbidity: What do We Really Know?

    Autism spectrum disorder (ASD) is a common comorbid condition in people with Fragile X syndrome (FXS). It has been assumed that ASD symptoms reflect the same underlying psychological and neurobiological impairments in both FXS and non-syndromic ASD, which has led to the claim that targeted pharmaceutical treatments that are efficacious for core symptoms of FXS are likely to be beneficial for non-syndromic ASD as well. In contrast, we present evidence from a variety of sources suggesting that there are important differences in ASD symptoms, behavioral and psychiatric correlates, and developmental trajectories between individuals with comorbid FXS and ASD and those with non-syndromic ASD. We also present evidence suggesting that social impairments may not distinguish individuals with FXS with and without ASD. Finally, we present data that demonstrate that the neurobiological substrates of the behavioral impairments, including those reflecting core ASD symptoms, are different in FXS and non-syndromic ASD. Together, these data suggest that there are clinically important differences between FXS and non-syndromic ASD that are masked by reliance on the categorical diagnosis of ASD. We argue for use of a symptom-based approach in future research, including studies designed to evaluate treatment efficacy. Keywords: Fragile X syndrome, autism spectrum disorder, comorbid conditions, language and communication impairments, psychiatric conditions

Clinical Insights into the Similarities and Differences for Diagnosis and Treatment

While it has long been known that individuals with Fragile X syndrome (FXS) often exhibit characteristics of autism spectrum disorder (ASD), only recently has the possibility been raised that the two conditions may have considerably more overlap than previously thought. Scientists at various Fragile X (FX) centers are studying whether this overlap may extend beyond mere behavioral similarities and perhaps include genetic or biological components as well. That research may prove to have far-reaching effects.

Meanwhile, parents, educators and clinicians in the FX field have continued to note the similarities and differences between the two conditions so they can plan appropriate interventions based on the specific characteristics and needs of each individual. It was in that spirit that a well-attended panel discussion at the 13th International Fragile X Conference in Miami pondered the topic: FXS and ASD: Clinical Insights into the Similarities and Differences for Diagnosis and Treatment.

The discussion provided clinical perspectives on the behavioral differences between FXS and what are thought to be core features of ASD. There is still much to be learned about identifying behaviors that suggest the presence or absence of ASD in FXS.

As the science advances, researchers and clinicians will achieve a deeper understanding of the overlap between the two conditions, and how that overlap affects both of them. Moderator Vicki Sudhalter, PhD, led a distinguished panel of clinicians that included Tracy Stackhouse, MA/OTR, Sarah Scharfenaker, MA-CCC-SLP, Walter Kaufman, MD, and Richard Belser, PhD. Here are the key points that came out of the panel discussion:

  • Fragile X syndrome causes a range of functioning across domains. It is a specific, identifiable condition with a known genetic cause. Autism spectrum disorder is identified by a cluster of symptoms rather than a specific condition, and is believed to have many causes, most of them unknown. There is overlap, in that some individuals with FXS have ASD, and some do not, though FXS is known to be the leading known single gene cause of ASD.
  • Clinicians must understand the differences between the two conditions in order to avoid misdiagnosis and improper treatment. Likewise, clinicians must appreciate the similarities. Harnessing what is known about ASD in particular, given its larger cache of treatment strategies, can help advance treatment and educational plans as appropriate.

    The core deficit in ASD is social interaction. The core deficit in FXS is intellectual function and hyperarousal/anxiety. A key point related to these differences: People with FXS tend to be deeply desirous of human interaction, but the social anxiety that also typifies the condition often causes them to act otherwise, which prevents success. People with ASD are largely unaware of the function others serve in relation to themselves, hence they rarely seek social interaction.

  • Eye contact is a key element of social interaction, and though “poor” eye contact is symptomatic of both FXS and ASD, the type of eye contact is substantially different. People with FXS tend to avoid eye contact, looking off in another direction to cope with their social anxiety, while people with ASD are unaware of why they should use eye contact as a source of information or interaction. Insisting on eye contact with those who have FXS is most always counterproductive, leading to greatly heightened anxiety.
  • Even when avoiding eye contact, people with FXS tend to be acutely aware of their surroundings. Like a good politician or salesperson, a person with FXS can read a room effectively, accurately gauging others’ moods and anxiety levels. They long to participate, to joke and be joked with. They want to be inside a social circle-but they typically need a great deal of acceptance, invitation and training to be successful at it. In contrast, people with ASD more often really do want to be left alone.
  • Imitation is generally a strength for those with FXS and not often seen in people with ASD. If imitation is not seen in those with FXS, it should be an impetus to conduct additional testing and treatment plans.
  • Teachers and caregivers often say they don’t need to know about FXS because they have previously had children with ASD in their classes or homes. But interventions appropriate for children with FXS may be quite different from those appropriate for children with ASD. For example, a shaping procedure is often used to increase eye contact in children with ASD. In contrast, our experience with children with FXS has shown us that working to increase eye contact in this population can be counterproductive.
  • Both FXS and ASD are typified by repetitive behaviors, but in FXS, this is most commonly manifested as hand-flapping and body-stiffening. Those with FXS tend to exhibit repetitive behaviors due to excitement, anxiety, or difficulty “stopping” or inhibiting their behavior. People with ASD engage in those behaviors as well, but for more varied reasons.
  • At base, most FXS behavioral issues are traceable to the twin challenges of managing anxiety and hyperarousal. Autism spectrum disorder is more complex and multi-faceted in its behavioral roots and manifestations, thereby making it essential to delineate the function of the behavior before formulating a treatment plan.
  • The crucial point for teachers, therapists and others involved in the care of those with FXS is not to lump them in with ASD as more or less a common diagnosis requiring a common set of interventions. Fragile X syndrome is still best treated utilizing what is known specifically about the condition.

 Often when a child is diagnosed with FXS, parents call the NFXF and ask us about medication that might help treat or cure their child. There are many different aspects of medical treatment for FXS.

These include treatment of behavioral/mental health issues,

treatment for medically associated issues such as seizures, and medication treatments being investigated in “clinical trials” to directly impact the effects of the FMR1 mutation that causes FXS.Here we will describe some of the classes of medications that may be prescribed by physicians. Please note that this discussion is for general informational purposes only, and that the NFXF does not evaluate, recommend or endorse specific medications. Please consult your individual medical providers to address your particular circumstances.

Medications for Behavioral/Mental Health Issues

Your child’s physician can consider various classes of medications to treat behavioral and mental health conditions associated with Fragile X syndrome. Some childen with FXS benefit from medications that treat ADD, ADHD and other attention disorders. Other children who experience general anxiety, social anxiety, OCD and other perseverative disorders may benefit from different types of anti-anxiety medications. Parents often have to work with their child’s doctor in trying more than one medication before finding the best fit for their child. For children facing more significant psychiatric challenges, a number of available “anti-psychotic” medications may be of value.

Treatment of Related Health Issues

Children with FXS have a higher incidence of various medical/health issues that often require medications. Prominent among these are anti-seizure medications and antibiotics for recurrent ear and sinus infections. Some babies with FXS also have problems with gastrointestinal reflux and may be prescribed medication to help treat their symptoms.

Clinical Trials for Medications

Families often read or hear about medications to treat FXS being developed or actively used in research trials. Many of these medications are under investigation for their potential to treat the symptoms of the condition, particularly its cognitive and behavioral aspects. It is therefore important to understand that clinical trial medications are not available through your health care provider.

A clinical trial is a study in which the participants are given the drug for a specific period of time and are carefully monitored for both positive and negative responses. The trials proceed through different phases to assess appropriate dosages, possible toxicity, clinical outcomes, etc. Clinical trials usually occur within a medical center, often where there is a Fragile X Clinics and a researcher (a “P.I.” or primary investigator) who heads up the study. We have more information about clinical trials and possible opportunities to participate on our Opportunities for Families page.