Alternative Names
Martin-Bell syndrome; Marker X syndrome; FRAXA Syndrome; Fragile X; fra(X) syndrome; FXS; X-linked mental retardation and macroorchidism
Symptoms & Characteristics
Fragile X syndrome is a genetic condition involving mutations in a gene on the X chromosome. Fragile X syndrome is the most common form of inherited mental retardation in males and a significant cause of mental retardation in females.
- Fragile X syndrome causes a range of developmental problems including learning disabilities and mental retardation.
- Affected people may have anxiety and hyperactive behavior such as fidgeting, excessive physical movements, or impulsive actions. They may also have attention deficit disorder, which includes an impaired ability to maintain attention and difficulty focusing on specific tasks.
- About 1/3 of affected males also have autism or autistic-like behaviors that affect communication and social interaction.
- About 15% of affected males and 5% of affected females have seizures.
- Many affected males have characteristic physical features that become more apparent with age. These features include a long and narrow face, large ears, prominent jaw and forehead, unusually flexible fingers, and enlarged testicles (macroorchidism) after puberty.
Treatment
There is currently no cure for Fragile X syndrome; however, early diagnosis, routine surveillance and treatment may help to manage some of the symptoms. Supportive therapy may include:
- Early educational intervention, special education, and vocational training aimed at the particular needs of individuals with Fragile X syndrome.
- Individualized drug therapies for the management of behavioral issues.
- Anticipatory management for behavioral difficulties - for example, the avoidance of excessive stimulation or sudden change whenever possible.
- Routine treatment of medical problems.
Individuals with poorly controlled seizures may be advised to avoid folic acid.
How Common Is It?
Fragile X syndrome occurs in approximately 1 in 4,000 males and 1 in 8,000 females.
Genetics & Inheritance
Fragile X syndrome is caused by mutations in the FMR1 gene on the X chromosome at the location q27.3.
- The FMR1 gene produces a protein called the fragile X mental retardation 1 protein. At this time, the function of this protein is not well understood
In the FMR1 gene, there is a particular region that contains a DNA segment of three nucleotides (the building blocks of DNA) that are repeated multiple times. These repeats are called CGG trinucleotide repeats.
The normal number of CGG repeats in the FMR1 gene ranges from 5 to 40.
In people with fragile X syndrome, the CGG segment is repeated more than 200 times.
- The abnormally expanded CGG segment "turns off" (silences) the FMR1 gene, which prevents the gene from producing the fragile X mental retardation 1 protein. Complete loss or a shortage (deficiency) of this protein disrupts nervous system functions and leads to the signs and symptoms of fragile X syndrome.
Of note, in a small percentage of cases, other types of mutations cause fragile X syndrome. These mutations delete part or all of the FMR1 gene. As a result, no protein is produced or the protein's function is impaired.
Males and females with 41 to 55 repeats are said to be in the "grey zone" (also called intermediate range).
- No consensus exists regarding the precise size of repeats that should be considered intermediate. Some researches define the "grey zone" as 41 to 58 repeats.
- Some studies have suggested that females with over 35 repeats are at risk to develop premature ovarian failure, in which menstrual periods stop by age 40
Males and females with 55 to 200 repeats of the CGG segment are said to have an FMR1 premutation.
- Most people with a FMR1 premutation are intellectually normal.
- In some cases, however, people with a FMR1 premutation have lower than normal amounts of the fragile X mental retardation 1 protein. As a result, they may have mild versions of the physical features seen in fragile X syndrome (such as prominent ears) and may experience emotional problems such as anxiety or depression. Some children with a premutation may have learning disabilities or autistic-like behavior.
- About 20% of females with a FMR1 premutation have premature ovarian failure.
- Males, and some females, with a FMR1 premutation have an increased risk of developing a disorder known as fragile X-associated tremor/ataxia syndrome (FXTAS). This disorder is characterized by progressive problems with movement (ataxia), tremor, memory loss, loss of sensation in the lower extremities (peripheral neuropathy), and mental and behavioral changes.
Fragile X syndrome is inherited in an X-linked dominant pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. The inheritance is dominant if one copy of the altered gene in each cell is sufficient to cause the condition. Unlike many other X-linked dominant conditions, more males are affected with Fragile X syndrome than females
- In females with a FMR1 premutation, the premutation can expand to greater than 200 in cells that develop into eggs. This genetic phenomenon of trinucleotide expansion is called anticipation. The exact risk for a female with a FMR1 premutation (also called a premutation carrier) to have an affected child is correlated with her FMR1 premutation CGG trinucleotide repeat number. This risk can be as high as 50%. Without a family history of Fragile X syndrome, about 1 in 240 to 1 in 460 females are believed to be Fragile X premutation carriers. This carrier frequency may be even higher in certain ethnic populations.
- By contrast, males with a FMR1 premutation are not considered at risk to have a child with Fragile X syndrome. Men pass the premutation only to their daughters. Their sons receive a Y chromosome, which does not include the FMR1 gene.
A
genetic consultation with a trained genetic professional is important for a
complete evaluation, accurate diagnosis, as well as discussion of the benefits
and limitations of testing and risk of recurrence within the family..
Diagnosis & Genetic Testing
Clinical genetic testing for Fragile X syndrome can be
broken down into two categories: diagnostic testing and carrier testing.
- Diagnostic testing may be used to confirm or rule out a clinical diagnosis in a person suspected to have the disorder. This testing is only available through an in person genetic consultation.
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Support & More Information
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Last Reviewed November 30, 2009