Fragile X Syndrome

Fragile X syndrome is the most common inherited form of mental retardation (1, 2). It affects about 1 in 4,000 males and 1 in 8,000 females and occurs in all racial and ethnic groups (1, 2).

Fragile X syndrome is a genetic disorder that runs in families. It is caused by an abnormality in a single gene.  

What are the characteristics of fragile X syndrome?
Children and adults with fragile X syndrome have a number of signs and symptoms ranging from mild to severe. Males tend to be more severely affected than females. Common characteristics include:

• Some degree of mental retardation or learning disabilities.
• Behavioral problems, such as difficulties paying attention and frequent tantrums.
• Autistic-like behaviors, such as hand flapping and hand biting.
• Delays in learning how to sit, walk and talk.
• Speech problems.
• Anxiety and mood problems.
• Sensitivity to light, sounds, touch and textures.
• Subtle physical features, sometimes including a long narrow face, large ears, a high arched palate, flat feet, and overly flexible joints (especially the fingers). Males tend to develop enlarged testicles after puberty.

Girls with fragile X syndrome generally have fewer physical signs of the disorder than males, though some have large ears. While most males with fragile X syndrome have mental retardation or serious learning disabilities, only about one-third to one-half of affected females do (2, 3). However, some affected girls with normal intelligence have learning disabilities involving math, attention difficulties, emotional problems (such as anxiety, depression and shyness), and poor social skills (4).

Do children with fragile X syndrome have medical problems?
Most children with fragile X syndrome do not have serious medical problems and generally have a normal life span. However, about 20 percent develop seizures, which generally can be controlled with medications (5). Children with fragile X syndrome may be at increased risk for chronic inner ear infections (otitis media) and may require the surgical insertion of drainage tubes (tympanostomy).

Heart murmurs may occur more frequently and are often caused by a condition called mitral valve prolapse (4, 5). This condition usually is not life-threatening, but individuals with mitral valve prolapse generally need to take antibiotics before dental care.

How is fragile X syndrome diagnosed?
Fragile X syndrome is diagnosed with a blood test. The blood sample is sent to a laboratory where the sample is analyzed to see if the gene abnormality is present. This test is available at most major medical centers. A health care provider, genetic counselor or the National Fragile X Foundation can refer a family for testing.

What causes fragile X syndrome?
In 1991, a March of Dimes-supported researcher discovered that fragile X syndrome is caused by a mutation (change) in a gene (called FMR-1) located on the X chromosome (6). Each person has 23 pairs of chromosomes, or 46 individual chromosomes. One pair, referred to as the sex chromosomes (called X and Y), determines whether a person is male or female. Normally, females have two X chromosomes, and males have one X chromosome and one Y chromosome.

A female who inherits one X chromosome with the abnormal FMR-1 gene has, in effect, a spare X with the normal gene. Therefore, females are affected by fragile X syndrome less frequently than males, and when affected, tend to have less severe symptoms. Males are generally more severely affected because they have one X chromosome containing only the abnormal gene.

The mutation that causes fragile X syndrome is a genetic “stutter” in which a small section of genetic material within the gene is repeated too many times. Most individuals who do not have fragile X syndrome have between six and 45 repeats of this section of three “letters” (called a trinucleotide repeat) that help spell out the gene (7).

When an individual has more than about 200 repeats, the gene turns off and fails to make the protein it usually makes. It is not known how lack of this protein causes the symptoms of fragile X syndrome, but studies suggest that this protein may help regulate communication between nerve cells in the brain (5).

Fragile X syndrome gets its name from the appearance of the section of the X chromosome where the gene mutation occurs. In certain conditions, under a microscope, the section of the chromosome looks fragile, as if it is dangling by a thread. 

How is fragile X syndrome inherited?
Individuals with a family history of this disorder should consult a genetic counselor to learn more about the risks to their offspring.

• Normal number of repeats. Individuals with a normal number of repeats (6 to 45) cannot pass fragile X syndrome on to their offspring. The number of repeats in the offspring generally does not change.
• Intermediate number of repeats or “gray zone”: When an individual has more than about 45 repeats but fewer than 55 repeats, the number of repeats can sometimes expand slightly when passed from parent to child. Individuals who have between about 45 and 55 repeats are considered in a “gray zone.” These individuals have not been found to have a child with fragile X syndrome. However, the number of repeats can grow with each generation, so their grandchildren could be at risk (7).
• Pre-mutation. Individuals with between about 55 and 200 repeats have what is called a pre-mutation (7). Both men and women can be carriers of the pre-mutation. About 1 in 250 women and 1 in 800 men carries the pre-mutation (8). However, only women who carry the pre-mutation are at risk for having a child with fragile X syndrome. 
  
  A pre-mutation carrier mother has a 50 percent chance of passing along the abnormal gene to her baby during each pregnancy. Some children who inherit the abnormal gene have a pre-mutation and no symptoms of fragile X syndrome. However, the number of repeats is likely to expand when the gene is passed from mother to child. As a result, some children of carrier mothers inherit the full mutation (more than 200 repeats) and show symptoms of fragile X syndrome.
  
  A male pre-mutation carrier passes on the pre-mutation to all of his daughters but to none of his sons. The daughters generally have no symptoms of fragile X syndrome, but they are carriers of a pre-mutation that may be passed on to their children. Unlike in females, in males the pre-mutation does not usually expand in size when passed on to their daughters. Sons of men with the pre-mutation do not inherit it because they do not get an X chromosome from their father.
• Full mutation. Individuals with more than 200 repeats have the full mutation. A woman with a full fragile X mutation has a 50 percent chance of passing along the full mutation in each pregnancy. If a man with a full mutation has children, he will pass the pre-mutation on to all of his daughters. For reasons that are not understood, the full mutation shrinks back to a pre-mutation in sperm. His sons are not at risk because they do not inherit the X chromosome from their father.

Do individuals with the pre-mutation have health risks?
Individuals with the pre-mutation do not have fragile X syndrome. However, recent studies suggest that some may have subtle behavioral or learning problems (7, 8).

Recent studies also suggest that about 30 percent of males over age 50 with the pre-mutation develop a neurological disease consisting of tremor and uncoordinated muscle movement (7). A small number of women with the pre-mutation also may develop this disorder, though they tend to be older than affected men and have milder symptoms.

In addition, about 20 percent of women with the pre-mutation develop ovarian failure and early menopause (before age 40), which can affect fertility (1, 7). Individuals with the full mutation generally do not develop the neurological disorder or ovarian failure.

When is fragile X testing recommended?
A health care provider may recommend that a child be tested for fragile X syndrome (1, 2):

• If the child has mental retardation, developmental delay or autism
• Especially if the child has physical or behavioral characteristics of fragile X syndrome
• If there is a family history of fragile X syndrome or mental retardation of unknown cause

A provider recommends testing if a woman who is planning pregnancy has a family history of fragile X syndrome or mental retardation or if she shows possible symptoms of fragile X syndrome. Testing also is recommended for women with reproductive or fertility problems that could be related to early ovarian failure, and for men and women with tremor, especially if they have a family history of fragile X syndrome or mental retardation.

Can fragile X syndrome be diagnosed before birth?
Prenatal tests (amniocentesis and chorionic villus sampling) can determine whether the baby of a carrier mother has inherited the full mutation or a pre-mutation. However, it's important to remember that individuals with the full mutation, particularly females, do not always have mental retardation.

How is fragile X syndrome treated?
There is currently no cure for fragile X syndrome. However, an individualized treatment plan, beginning during the preschool years, can help affected children reach their full potential. Most children with fragile X syndrome can benefit from treatment by a team of health professionals and special educators. The members of the team may include speech/language therapists, physical and occupational therapists, special educators, psychologists and pediatricians.   

Some children with fragile X syndrome benefit from medications that improve their behavioral symptoms so that they are better able to learn. Some commonly used medications include antidepressants, stimulants (such as Ritalin, used for hyperactivity), and antiseizure drugs (also used for behavioral and mood problems). 

Does the March of Dimes support research on fragile X syndrome?
March of Dimes research grantees are investigating how loss of the protein made by the fragile X gene may interfere with communication between nerve cells in the brain, resulting in mental retardation and other features of the syndrome. The goal of this research is to develop an effective treatment. Another grantee is studying how the gene mutation contributes to autistic-like behaviors, in order to improve the diagnosis and treatment of both fragile X syndrome and autism. 

For more information:
The National Fragile X Foundation
(800) 688-8765

FRAXA Research Foundation
(978) 462-1866

References

1. American College of Obstetricians and Gynecologists (ACOG). Screening for Fragile X Syndrome. ACOG Committee Opinion, number 338, June 2006.
2. Sherman, S., et al. American College of Medical Genetics Practice Guideline: Fragile X Syndrome: Diagnostic and Carrier Testing. Genetics in Medicine, volume 7, number 8, October 2005, pages 584-587.
3. Fragile X Research Foundation. About Fragile X. Accessed 3/30/07.
4. National Fragile X Foundation. What Is Fragile X Syndrome? Updated 6/1/06.
5. National Institute of Child Health and Human Development (NICHD). Families and Fragile X Syndrome. NIH Publication No.96-3402, last updated 8/04/06.
6. Verkerk. A.J.M.H., et al. Identification of a Gene (FMR-1) Containing a CGG Repeat Coincident with a Breakpoint Cluster Region Exhibiting Length Variation in Fragile X Syndrome. Cell, volume 65, May 1991, pages 905-914.
7. Centers for Disease Control and Prevention (CDC). Fragile X Syndrome. September 1, 2006.
8. McConkie-Rosell, A., et al. Genetic Counseling for Fragile X Syndrome: Updated Recommendations of the National Society of Genetic Counselors. Journal of Genetic Counseling, volume 14, number 4, August 2005, pages 249-270.

April 2007