An Overview of Fragile X Syndrome

Managing Intellectual Disability and Other Symptoms

Fragile X syndrome is a medical condition that causes intellectual disability and other medical problems. It is the most common kind of genetically inherited intellectual disability, and the second-most common type of intellectual disability overall (after Down syndrome). Fragile X syndrome is estimated to occur in about one male in 5,000 to 7,000 and in about one female in 4,000 to 6,000. It is named for the unusual appearance of the X chromosome of people with fragile X syndrome (seen in certain laboratory tests).

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Symptoms

People with fragile X syndrome can have a variety of symptoms that can differ in severity. Not everyone with fragile X syndrome will experience all these potential issues. The problems present and their severity also may change over an individual’s lifetime. One good piece of news is that people with fragile X syndrome appear to have a normal or near-normal life span.

Because of the nature of the genetic problem causing fragile X syndrome, girls tend to be less severely affected than boys.

Brain and Nervous System

Developmental delay and intellectual disability are major issues in fragile X syndrome. For example, a child might first learn to talk or walk at a much later age than normal.

Some people with fragile X syndrome have normal intellectual functioning. At the other extreme, some people have severe intellectual disability. According to estimates, intellectual disability occurs in about 85% of males and in about 25% of females.

Behavioral issues are another big category. Some of the possible issues include:

  • Attention problems
  • Hyperactivity
  • Anxiety
  • Social avoidance
  • Self-injurious and/or aggressive behavior

Researchers estimate that about 50% of males and 20% of females with fragile X syndrome have an autism spectrum disorder as well. In fact, though autism has many different multi-factorial causes, fragile X syndrome is the most common known cause of the condition. It accounts for about 2-3% of all cases of autism.

General Medical Issues

Some of the medical issues that can occur in people with fragile X syndrome include:

  • Seizures
  • Recurrent ear infections
  • Strabismus (crossed eyes)
  • Loose, hyperextensible joints
  • Scoliosis
  • Gastroesophageal reflux
  • Sleep disorders
  • Flat feet
  • Abnormally large testes
  • Heart problems like mitral valve prolapse

Some people with fragile X syndrome also possess certain characteristic facial features, like a long face with a broad forehead, large ears, and prominent jaw. However, not all people with fragile X syndrome have features like this, and these physical characteristics aren’t always obvious at birth.

Causes

Fragile X syndrome is caused by a problem in a gene known as fragile X mental retardation 1 (FMR1). This gene contains the genetic information to make a protein known as fragile X mental retardation protein (FMRP).

Because of a genetic error, the FMR1 gene can’t make FMRP the way it normally would. Most commonly, the genetic error causes an abnormal repeated series of nucleotides (components of DNA) to be inserted in the normal DNA sequence. This specific mutation is called a CGG repeat. In people with fragile X syndrome, this sequence is repeated over 200 times (compared to a normal repeat number of 5 to 44).

Because of this, the FMR1 gene can’t make FMRP protein as it would in someone without fragile X syndrome. In people with fragile X syndrome, the FRMR1 gene doesn’t make any FMR1 protein at all, or it makes it in lower amounts that normal. Individuals who can make some FMRP tend to have less severe symptoms than those who cannot make any functional protein.

FMRP is an important protein, especially in the brain. It plays key roles in regulating the production of other proteins in brain cells. FMRP is critical for synaptic plasticity, the process by which neurons learn and retain information over time. Scientists are still learning more about how exactly FRMP affects brain development and brain function.

FMRP also is present in some other types of cells, like the testes, and lack of the protein in these other parts of the body can lead to other symptoms.

More Genetics

The FMR1 gene is found on the X chromosome. That’s the sex chromosome, of which women have two copies and men have one copy. In men with fragile X syndrome, only one FRMP gene is available. However, women usually have some copies of the FRMP gene that work normally, because they receive an unaffected X chromosome from one of their parents. That’s why they tend to have fewer and less severe symptoms.

Another factor complicates the understanding of fragile X syndrome. Some people have what is called a “premutation” of the FMR1 gene. This is not a full-blown mutation causing fragile X syndrome, but it isn’t quite normal. (People who have between 55 and 200 CGG repeats in the FMR1 gene have such a “premutation.”) Those people may pass fragile X on to their children, and they are at risk of certain medical conditions.

Diagnosis

It’s likely that your clinician will have to explore a wide range of possibilities before coming to a diagnosis. That’s because intellectual disability and developmental delay can be caused by many different sorts of problems. Some of these are genetic, but others are environmental (e.g., certain kinds of prenatal infections). So it may take a while to narrow in on a diagnosis of fragile X syndrome.

Diagnosis of fragile X syndrome starts with a thorough medical history and a clinical exam. Some symptoms and characteristics of fragile X syndrome might be apparent at birth. However, these might not be obvious right away. This may make fragile X syndrome difficult to diagnose in the newborn period. It may take longer for symptoms to emerge and for the diagnostic process to begin.

Family history is an important part of the diagnostic process, including the history of intellectual disability in the family. However, other family problems might also point toward fragile X syndrome as a possibility. For example, a history of tremor in an older relative might indicate a problem with the FMR1 gene, which might make fragile X syndrome more likely. A relative with early menopause or fertility issues might be another clue.

It’s key that your physician gets a clear idea of all the problems involved. This is critical, since not everyone with fragile X syndrome has identical symptoms. Sometimes these medical problems can provide clues about the underlying cause of the problem. Other times, subtle physical differences can give a clue about the presence of fragile X syndrome.

A variety of tests are sometimes used to help narrow in on a diagnosis. These will depend on the specific symptoms present. Such tests can sometimes rule out other possible causes. For example, a child might receive tests like the following:

  • Brain imaging
  • Thyroid function tests
  • Blood tests for metabolic diseases
  • Electroencephalography (EEG)
  • Heart echocardiogram

Genetic testing is essential for definitive diagnosis. This is done via a specialized genetic test of the FMR1 gene that detects the CGG nucleotide repeat inside the gene. It’s important that clinicians be thinking about the possibility of fragile X syndrome so that they can use this test to confirm the disease. In some cases, even more specialized genetic tests may be necessary to pick up the diagnosis.

It’s important that caregivers of a child give provide insights about developmental and behavioral issues. It’s also essential to look for symptoms that might indicate autism. Detailed tests of intellectual functioning and various psychiatric tests can also provide insight (e.g., IQ tests). These can help give an idea of the individual’s needs and potentials, as well as the types of interventions that might help. Often, specialists can aid in these assessments.

Treatment

Currently, no specific treatment is available to address the root causes of fragile X syndrome. However, a team of medical professionals will help your loved one receive the best possible support and care. Working with people who have specialized training in childhood genetic diseases like fragile X syndrome can be extremely beneficial. It’s important that infants with fragile X syndrome receive referrals to early intervention programs, which can provide support in a child’s development.

Treatment of fragile X syndrome requires work from a variety of specialists. For example, some of the following are often helpful:

These therapies can help an individual with fragile X manage some of their symptoms and maximize their quality of life.

As children with fragile X become old enough to enter preschool and school, they will need formalized evaluation for specifically tailored therapies and services. This is written up in something called an individualized education plan (IEP). This provides a plan so that children with fragile x syndrome can receive the best support while also being included in general education to the extent that is possible.

Sometimes, medications are helpful for some of the problems of fragile X syndrome. For example, depending on the circumstances, this might include:

  • Psychostimulants (like methylphenidate) for ADHD-like symptoms
  • Serotonin reuptake inhibitors for aggression, self-injury, or anxiety
  • Anti-seizure medications
  • Antibiotics for recurrent ear infections
  • Proton pump inhibitors for gastrointestinal problems

Regular monitoring is also an essential part of ongoing care. For example, your health care provider will need to monitor for the development of potential heart problems, like mitral valve prolapse.

Additionally, it’s helpful to network with other families. The National Fragile X Foundation provides much helpful support, advocacy, and information for families dealing with a fragile X syndrome diagnosis.

Inheritance, Fragile X-Related Conditions, and Screening

Inheritance

The genetic inheritance of fragile X syndrome is quite complicated and unusual. It’s very helpful to talk to a genetic counselor about your specific situation and see whether you might need to get genetic testing yourself. That’s particularly important because having a person with fragile X syndrome in the family might mean you're at risk of certain health conditions. That's why you may need to get tested even if you have no plans of having a child.

Fragile X syndrome follows most of the patterns of what is called an X-linked dominant disorder. That means that inheriting an affected X chromosome from either parent might cause symptoms of fragile X syndrome. However, a woman who inherited an affected gene might not have fragile X syndrome or might have only very mild symptoms. Men can only inherit an X chromosome from their mother. A man who inherits an affected X chromosome will almost certainly have symptoms.

Fragile X-Related Conditions

Something else complicates the inheritance of fragile X syndrome—premutations. People with premutations don’t have fragile X syndrome, and they may not have any medical problems at all.

However, people with premutations are at risk of having certain other medical problems. For example, they may be at risk of a medical condition called fragile X-associated tremor/ataxia syndrome (FXTAS), which leads to tremor and difficulty with balance later in life. Women with premutations are at risk of another medical condition called fragile-X associated primary ovarian insufficiency (FXPOI). This can cause premature menopause or early ovarian failure.

Additionally, a premutation can be a concern because sometimes it will be transmitted to children as a full mutation. In that case, a child might get fragile X syndrome from a parent even though neither parent has fragile X syndrome.

Screening and Prenatal Counseling

The American Congress of Obstetricians and Gynecologists recommends genetic counseling and screening for fragile X for all women who have a personal or family history of the disease. They also recommend it for women who have a personal or family history of unexplained intellectual disability, autism, or ovarian insufficiency before the age of 40. It’s important to get tested to understand your own medical risks as well as those of any potential offspring.

Prenatal diagnosis may be possible for women known to be carriers of the FMR1 gene mutation. It may also be possible to use in vitro fertilization and preimplantation services to ensure the conception of children without the condition.

A Word From Verywell

It can be heartbreaking to learn of a diagnosis of fragile X syndrome in your family. But it’s hard to know right away how much this will affect a person’s life. Learning what you can about the condition and its treatment may help you feel more empowered as you advocate for your child. 

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