Fragile X syndrome is a genetic condition associated with cognitive impairment, learning and behavioral challenges, and several physical features. It is the most common cause of inherited intellectual disability and autism spectrum disorders (ASDs) and it is estimated to affect 1 in 4,000 males and 1 in 8,000 females.
People with fragile X have a generally normal life expectancy.
Fragile X is caused by mutations in the FMR1 gene, located on the X chromosome — one of the sex chromosomes, with the other being the Y chromosome. The syndrome was named fragile X due to the presence of what appeared to be a broken or fragile segment in the X chromosome of some patients, which was later found to be the exact location of the FMR1 gene.
This gene provides the instructions for making a protein called FMRP, which regulates the production of proteins involved in nerve cell communication. FMR1 mutations impair the production of FMRP, leading to cognitive, developmental, and behavioral symptoms.
To develop the disease, a child only has to inherit one mutated copy of the FMR1 gene.
Since men only have one X chromosome (inherited from the mother), those who inherit the mutated gene will have more severe disease. In women — who have two X chromosomes, one from the mother and one from the father — a healthy FMR1 gene copy can partly compensate for the mutated copy.
A certain type of milder FMR1 mutations, called premutations, do not lead to the development of fragile X, but increase the risk of developing late-onset related conditions, called fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. People with a FMR1 premutation are called premutation carriers.
Notably, since a premutation can suffer genetic changes in cells that develop into eggs, and potentially become a fragile X-causing mutation, female carriers also have up to a 50% chance of passing the full mutation to their children. These children will either be premutation carriers, or develop fragile X syndrome.
It is estimated that 1 in 130 to 250 women, and 1 in 250 to 800 men, are premutation carriers.
Symptoms of fragile X, which are more frequent and generally more severe in males, are usually not apparent until early childhood, when developmental and physical features become more obvious. They also differ in severity and occurrence among patients.
Common symptoms include intellectual disability, which can range from mild to severe, delayed motor, language, and speech development, and behavioral problems, such as hyperactivity, attention difficulties, anxiety, mood instability, impulsivity, obsessive-compulsive disorder, and depression.
ASDs and autistic behaviors, including communication and social difficulties, poor eye contact, repetitive movements, and repetition of phrases and noises said by others, are also common.
Patients are often highly sensitive to external stimuli, such as loud noises and bright lights, and also frequently exhibit self-injuring and aggressive behaviors.
Fragile X is also associated with characteristic physical features that become more pronounced with age and are more frequent in males. These may include a long face, prominent forehead, chin, and ears, unusually flexible fingers, strabismus (improper eye alignment), flat feet, and larger-than-normal testes in males.
Other symptoms can include frequent ear and urinary infections, low muscle tone, vision and dental problems, scoliosis (a sideways curvature of the spine), groin hernias, and heart problems. Seizures occur in 14–18% of males and about 6% of females.
The only conclusive way of diagnosing fragile X is genetic testing to identify disease-causing mutations in a person’s copies of the FMR1 gene. DNA testing is also highly reliable in identifying premutation carriers, which can help to estimate a person’s chances of having a child affected by the disease.
This type of test can also be conducted before birth to assess whether an unborn baby has a FMR1 premutation or a fragile X-causing mutation.
Currently, no cure exists for fragile X syndrome, so treatment generally aims to ease symptoms, particular the behavioral and mental health challenges, and to improve patients’ quality of life.
Management of fragile X often includes special education, speech, occupational, and behavior therapy, and sensory integration training. Early intervention is particularly important.
The search for more targeted treatments is ongoing, with clinical trials of potential treatments currently underway.
Last updated: April 16, 2021
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