Fragile X Syndrome

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

Fragile X syndrome is a genetic disorder that runs in families. It is different from Down syndrome, another common genetic cause of mental retardation. Down syndrome is generally caused by an extra chromosome (chromosomes are the structures in cells that contain the genes), while fragile X syndrome is caused by an abnormality in a single gene.

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. 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. A female, therefore, tends to be less often affected by fragile X syndrome than a male and, if affected, less severely than a male. Males have one X chromosome containing only the abnormal gene, so they are generally more severely affected.

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, like it is dangling by a thread.

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 unaffected individuals have between six and 40 repeats of this section of three letters (called a trinucleotide repeat) that help spell out the gene. 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 communication between nerve cells in the brain may be affected.

Fragile X syndrome can be passed from a carrier mother to her children. About one in 250 women in this country carries the fragile X gene. A woman is considered a carrier of fragile X syndrome if she has either a pre-mutation (60 to 200 trinucleotide repeats within her FMR-1 gene) or a full mutation (greater than 200 trinucleotide repeats within her FMR-1 gene). A carrier of a pre-mutation generally has no symptoms of fragile X syndrome, though recent studies suggest that women who carry this pre-mutation may be at increased risk of early menopause (prior to age 40). Approximately one-third to one-half of female carriers of a full mutation will exhibit signs of fragile X syndrome, but are usually less severely affected than males with full mutations.

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 will have a pre-mutation and no symptoms of fragile X syndrome. However, the number of repeats may 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 woman who carries a full fragile X mutation has a 50 percent chance of passing along the full mutation in each pregnancy. Most boys who inherit the full mutation display symptoms of fragile X syndrome, while only up to half of girls do.

A man also can be an unaffected carrier of a pre-mutation in the fragile X gene. An unaffected carrier male will pass 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 his daughters. Very recent studies suggest that some males over age 50 with the pre-mutation may exhibit a neurological disease consisting of tremor and uncoordinated muscle movement.

The genetics of fragile X syndrome are complicated. A couple with a family history of fragile X syndrome should consult a medical geneticist or a genetic counselor to learn more about the risks of this disorder in their offspring.

Children and adults with fragile X syndrome have varying degrees of mental retardation or learning disabilities and behavioral and emotional problems, including autistic-like features. Males tend to be more severely affected than females.

Young children with fragile X syndrome often have delays in developmental milestones, such as learning how to sit, walk and talk. Affected children may have frequent tantrums and difficulties paying attention. They often are highly anxious and easily overwhelmed by what's going on around them. They may have speech problems and unusual behaviors, such as hand flapping and hand biting.

While many children with fragile X syndrome do not look different from their peers, some have subtle physical signs. These include a long narrow face, large ears, a high arched palate, flat feet and overly flexible joints (especially the fingers). Some of these features do not become obvious until after puberty, when males tend to develop enlarged testicles.

Girls with fragile X syndrome have fewer physical signs of the disorder, 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. 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.

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. Children with fragile X syndrome also may be at increased risk of inner ear infections (otitis media), vision problems (including near-sightedness and .lazy eye.) and digestive disorders (including gastro-esophageal reflux).

A blood test identifies people who have either fragile X syndrome or who are carriers of the disorder. The blood sample is sent to a laboratory where the FMR-1 gene is analyzed to see if a mutation or pre-mutation is present. This test is available at most major medical centers. A doctor, genetic counselor or the National Fragile X Foundation (see below) can refer a family for testing.

A health care provider may recommend that a child be tested for fragile X syndrome if he has mental retardation, developmental delay or autism, especially if the child has physical or behavioral characteristics of fragile X syndrome, or if there is a family history of fragile X syndrome or mental retardation of unknown cause. A health care provider also may recommend testing if a woman who is planning a pregnancy has a family history of fragile X syndrome or mental retardation or if she shows possible symptoms of fragile X syndrome.

Prenatal tests (amniocentesis and chorionic villus sampling) can determine whether the baby of a carrier mother has inherited the full mutation. However, the test cannot always determine whether a baby will be mentally retarded. While almost all boys who inherit the full mutation have mental retardation or serious learning disabilities, only about one-third to one-half of affected girls do.

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).

Two March of Dimes research grantees are currently investigating how loss of the protein made by the fragile X gene causes mental retardation and other features of the syndrome. Another is studying the speech and language problems associated with fragile X syndrome to develop improved forms of speech therapy for affected children.

For additional information, a family can contact:

1-800-688-8765

978-462-1866

American College of Medical Genetics.

. Policy Statement, July 28, 1994, accessed 4/17/03.

Crawford, D.

. Centers for Disease Control and Prevention, Human Genome Epidemiology Network, July 2001.

. About Fragile X. Accessed 4/21/03.

Hatton, D., et al. Problem Behavior in Boys with Fragile X Syndrome. American Journal of Medical Genetics, volume 108, 2002, pages 105-116.

. What Is Fragile X Syndrome? Updated 4/1/03.

. Facts About Fragile X Syndrome. Updated 9/3/02.

Saul, R.A., Tarleton, J.C.

, updated 4/7/03.

09-1779-03 6/03 (R 8/06)