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Fragile X Syndrome

What is Fragile X Syndrome?

Fragile X syndrome is a genetic disorder that can lead to developmental problems that can include behavioral challenges and impairment in intellectual abilities. Intellectual disability can range from mild learning disabilities to significant intellectual disability. Behavioral challenges can include anxiety and hyperactive behaviour (such as fidgeting).  Seizures may occur in a small number of affected males and females. Generally, males are more frequently and more severely affected than females. Females usually display less severe intellectual disability and a milder expression of the behavioral and physical issues associated with the disorder. Although this is true as a general rule, females (as much as one-third of the time) can develop significant intellectual disability.

 

 

Synonyms

  • Fragile X Syndrome
  • Martin-Bell syndrome
  • FRAXA syndrome

Fragile X syndrome is a genetic disorder that can lead to developmental problems that can include behavioral challenges and impairment in intellectual abilities. Intellectual disability can range from mild learning disabilities to significant intellectual disability. Behavioral challenges can include anxiety and hyperactive behaviour (such as fidgeting).  Seizures may occur in a small number of affected males and females. Generally, males are more frequently and more severely affected than females. Females usually display less severe intellectual disability and a milder expression of the behavioral and physical issues associated with the disorder. Although this is true as a general rule, females (as much as one-third of the time) can develop significant intellectual disability.

 

Acknowledgement of Fragile X Syndrome has not been added yet.

Fragile X syndrome is the most common form of inherited intellectual and developmental disability. The prevalence of fragile X syndrome is estimated to be approximately 1 in 3,600-4,000 males and 1 in 4,000-6,000 females in the United States. Although there are about twice as many males being affected than females, there are about four times as many females that appear to be carriers of an altered fragile X syndrome gene as do males (which is approximately 1 in 250 for females and 1 in 1000 for males). However, some females with a full mutation of the causative gene do not develop any symptoms of the disorder, likely due to retaining an intact copy of the gene on their second X chromosome.

Name Abbreviation
Fragile X Syndrome FXS
Martin-Bell syndrome FXS
FRAXA syndrome FXS

Fragile X syndrome is caused by a mutation in the FMR1 gene located on the X chromosome at Xq27.3.  Individuals affected with Fragile X syndrome have an increased number of copies of the DNA sequence CGG in the initial part of the FMR1 gene. Some people have a premutation, which is generally anywhere from 50-200 CGG repeats. This results in an unstable FMR1 gene. People with a premutation may have conditions known as “Fragile X-associated disorders.” Unfortunately, the number of the CGG sequence may increase from one generation to the next and the greater the number of copies of CGG, the greater the likelihood that full Fragile X syndrome will result. Thus, premutations may spontaneously reach the level of a full mutation in later generations, causing Fragile X syndrome.


An excessive number of CGG repeats (greater than 200) is referred to as a full mutation in the FMR1 gene. This triggers an action called methylation, in which the affected part of the gene is shut down. Methylation prevents the FMR1 gene from producing the FMR protein (FMRP).  As a result, the abundance of the protein gradually decreases. The FMR protein is involved in connecting nerve cells (neurons) in the brain and is essential for the proper development and health of the brain.

The specific symptoms and severity of the fragile X syndrome will vary from one person to another. Any particular individual will not develop all of the symptoms potentially associated with this disorder.

Children with fragile X syndrome can be characterized by developmental problems which include behavioral challenges and intellectual disability. Behavioral challenges can include social anxiety, poor eye contact, attention deficit hyperactivity disorder, autism spectrum disorders, and an increased risk of aggressive behavior. In males, intellectual disability can range minor to severe. In females, intellectual disability tends to be mild and often appear as shyness, mild learning disabilities, and social anxiety. Some children experiences speech delays or seizures. Delays are often seen in reaching developmental milestones.

Throughout an individual’s life, some of the symptoms for fragile X may become more apparent.  For instance, having a long and narrow face, large ears, a prominent jaw and forehead, unusually flexible fingers, and flat feet are all part of the symptoms.  For some cases, males’ testicles may become enlarged following puberty.

A diagnosis of fragile X syndrome should be considered in children and adults with unexplained intellectual disability, developmental delays or autism.

Almost all individuals with fragile X syndrome have a full mutation in the FMR1 gene that causes abnormal methylation, preventing the FMR1 gene from producing FMR protein. Molecular genetic testing can confirm a diagnosis by identifying the characteristic mutation in the FMR1 gene that causes the disorder. Historically, chromosome analysis under a microscope was used to diagnose fragile X syndrome. The disorder was given its name, fragile X, because some affected individuals had X chromosomes that appeared as though they had been “snapped” or “pinched” but were still intact. This technique is no longer used for diagnosis because it is much less accurate and more expensive than current molecular techniques.

Carrier testing for relatives that could bear fragile X syndrome premutations, or for carrier females with one fragile X chromosome but no disease symptoms, can also be performed.  

Currently, there are no specific treatments for fragile X syndrome patients. However, there are several alternatives that individuals may consider. Affected individuals may benefit from special education in order to avoid excessive stimulation of the brain, which may help behavioral problems. Medications including stimulants and selective serotonin reuptake inhibitors or SSRIs can help with anxiety or obsessive compulsive behaviors. Antipsychotic medications can help to treat self-injurious behavior, autistic symptoms, and aggressive behaviors. These medications can help to improve social interaction with others.  Medical management of ear infections, reflux, seizures, and high blood pressure is also recommended for individuals with fragile X syndrome.

Generally, life expectancy for people with fragile X is not specifically affected by the disorder. Countless affected individuals practise a healthy lifestyle. Nonetheless, some individuals are more prone to fragile X complications such as seizures.  However, regular medical checkups with doctors and awareness of their fragile X syndrome status improve outlook.

Individuals with fragile X syndrome may seek help from occupational therapists, speech pathologists, and psychologists. An occupational therapist can work with individuals on hypersensitivity and tactile defensiveness. In addition to this, the therapist can give advices and assistance on calming techniques, movement, fine motor development, and oral motor development.  A speech pathologist can help with language skills and speech (such as pronunciations). A psychologist can give support on behaviour, social emotions, education, and family.

Fragile X Syndrome. Genetic Home Reference website. Available at: http://ghr.nlm.nih.gov/condition/fragile-x-syndrome 

Fragile X Mental Retardation Syndrome. Online Mendelian Inheritance in Man (OMIM) website. Available at: http://www.omim.org/entry/300624 

Fragile X Syndrome. National Organization for Rare Disorders website.  Available at: https://rarediseases.org/rare-diseases/fragile-x-syndrome/


Hagerman R. Fragile X Syndrome. OrphaNet website. Available at: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=908.0 Accessed May 2016.

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