FRAGILE X SYNDROME

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Fragile X syndrome is the most common inherited form of intellectual disability (1, 2). It affects about 1 in 4,000 males and 1 in 6,000 to 8,000 females and occurs in all racial and ethnic groups (1).What are the signs and symptoms of fragile X syndrome?
Children and adults with fragile X syndrome have a number of mental and physical signs and symptoms ranging from mild to severe. Males tend to be more severely affected than females. Common mental symptoms include (1, 3):

 

• Some degree of intellectual disability or learning problems

• Behavioral problems, such as difficulty 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

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Individuals with fragile X syndrome may have subtle physical signs that tend to become more obvious with age. These may include (1, 3):

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• Large head

• Long, narrow face

• Large ears

• Prominent forehead and chin

• Overly flexible joints (especially the fingers)

• In males, enlarged testicles that develop after puberty

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Girls with fragile X syndrome generally have fewer physical signs of the condition than males. While most males with fragile X syndrome have intellectual disabilities, only about one-third to one-half of affected females do (3, 4). However, affected girls with normal intelligence may have some of the following symptoms (5):

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• Learning disabilities involving math

• Attention difficulties

• Speech delays

• Emotional problems, such as anxiety, depression and shyness

• Poor social skills

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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 15 percent of affected boys and about 5 percent of girls develop seizures, which often can be controlled with medication (5). Children with fragile X syndrome may be at increased risk for chronic inner ear infections and may need to have tubes placed in their ears (5).

 

Children with fragile X syndrome may have heart murmurs that often are caused by a condition called mitral valve prolapse (5). This condition usually is not life-threatening and, in most cases, does not require treatment.

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What causes fragile X syndrome?
Fragile X syndrome is caused by an abnormality in a single gene. In 1991, a researcher supported by the March of Dimes discovered that fragile X syndrome is caused by a mutation (change) in a gene called FMR-1 located on the X chromosome (6).

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Each person has 23 pairs of chromosomes, or 46 individual chromosomes. The pair of sex chromosomes (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. Because females have two X chromosomes, a female who inherits one X chromosome with the abnormal FMR-1 gene still has the other unaffected X chromosome. Therefore, females are affected by fragile X syndrome less frequently than males. When affected, females tend to have less severe symptoms than males. Males generally are more severely affected because they have only one X chromosome, and it contains the abnormal gene.

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The mutation that causes fragile X syndrome is a genetic “stutter.” This means that a small section of genetic material within the gene is repeated too many times. Most people who do not have fragile X syndrome have between 5 and 40 repeats of this section of the gene. People who have more than 200 repeats of the gene have fragile X syndrome. More than 200 repeats is called a full mutation. A full mutation causes the gene to turn off and not make the protein it usually makes. The protein normally is found in many types of cells but mostly in nerve cells (3). Scientists think the protein helps brain development and may help nerve cells in the brain communicate (3, 5).

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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.

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How is fragile X syndrome diagnosed?
Fragile X syndrome is diagnosed with a blood test. A blood sample is sent to a laboratory where it is checked for the gene mutation. The test is available at most major medical centers. A health care provider, genetic counselor or the National Fragile X Foundation can provide information on testing locations.

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Boys with fragile X syndrome usually are diagnosed at about 3 years of age (often at about 35 to 37 months) (7). Girls have milder symptoms and usually are diagnosed a little later (often at about 41 months) (7).

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

• • Normal number of repeats: Individuals with a normal number of repeats (5 to 40) cannot pass fragile X syndrome to their offspring. The number of repeats generally does not change when passed from parent to child.

  • Intermediate number of repeats: When a person has 41 to 58 repeats (called the gray zone), the number of repeats can sometimes increase slightly when passed from parent to child. These parents are not at risk of having a child with fragile X syndrome. However, the number of repeats can grow with each generation, so their grandchildren could be at risk.

  • Premutation: Individuals with 59 to 200 repeats have a premutation (3). Both men and women can be carriers of a premutation. About 1 in 250 women and 1 in 800 men carries a premutation (8). However, only women who carry a premutation are at risk for having a child with fragile X syndrome.

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A mother with a premutation has a 50-percent chance of passing the abnormal gene to her baby in each pregnancy. Some children who inherit the abnormal gene have a premutation 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. So the number of repeats can increase from a premutation to a full mutation (more than 200 repeats). Children with a full mutation have fragile X syndrome.

 

A father with a premutation passes it to all of his daughters but to none of his sons. Daughters generally have no symptoms of fragile X syndrome, but they are carriers of a premutation that they can pass on to their own children. Fathers with a premutation do not pass it to their sons because males do not get an X chromosome from their father.

 

Full mutation: Individuals with more than 200 repeats have a full mutation. A woman with a full mutation has a 50-percent chance of passing it to her baby in each pregnancy. Men with a full mutation generally do not reproduce.

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Do individuals with a premutation have health risks?
Individuals with a premutation do not have fragile X syndrome. However, they may be at increased risk of:

• Learning and behavioral problems: Individuals with a premutation generally have normal intelligence. However, some may develop subtle behavior or learning problems (1, 3, 5).

• Fragile X-associated tremor/ataxia syndrome: At least 30 percent of males over age 50 with a premutation develop a neurologic (nervous system) disease that causes tremors (shaking) and uncoordinated muscle movement (1). Between 4 and 8 percent of women with the premutation may develop this disorder, though they tend to be older than affected men and have milder symptoms (5).

• Premature ovarian failure: About 20 percent of women with a premutation develop premature (early) ovarian failure and early menopause, which means they happen before age 40. This can affect a woman’s fertility (1, 2).

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Individuals with a full mutation generally do not develop neurologic disease or premature ovarian failure and early menopause.

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When is fragile X testing recommended for children?
A health care provider may recommend testing a child for fragile X syndrome if the child has intellectual disabilities, developmental delay or autism. Testing is especially important if the child also has (9):

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• Physical or behavioral signs and symptoms of fragile X syndrome

• A family history of fragile X syndrome or intellectual disabilities of unknown cause

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When is fragile X testing recommended for women planning pregnancy?
Women who are planning pregnancy may be offered carrier screening for fragile X syndrome if they have:

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• A family history of fragile X syndrome or a disorder related to fragile X syndrome

• A family history of intellectual disabilities with no known cause

• A personal or family history of developmental delay or autism

• A personal history of reproductive or fertility problems that could be related to early ovarian failure

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Women and their partners who are found to be carriers of a fragile X mutation or premutation should talk to a genetic counselor. These health professionals help families understand the chances of a birth defect occurring in a pregnancy and can discuss the possibility of prenatal testing. Genetic counseling is available at most large medical centers and teaching hospitals. To find a genetic counselor, individuals can ask their health care provider or contact the National Society of Genetic Counselors.

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Can fragile X syndrome be diagnosed before birth?
Prenatal tests (amniocentesis and chorionic villus sampling [CVS]) can determine whether the baby of a carrier mother has inherited a full mutation or premutation. Occasionally, CVS cannot determine whether the baby has a large premutation or a full mutation. In these cases, providers may recommend follow-up with amniocentesis

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How is fragile X syndrome treated?
There is no cure for fragile X syndrome. However, an individualized treatment plan, beginning in 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 team may include speech/language therapists, physical and occupational therapists, special educators, psychologists and pediatricians.

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Some children with fragile X syndrome benefit from medications that improve their behavioral symptoms so they are better able to learn. Some commonly used medications include:

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• Antidepressants, used for anxiety and mood problems

• Stimulants (such as Ritalin), used for hyperactivity and attention problems

• Antiseizure drugs, used for behavior and mood problems

• Antipsychotics, used for aggression and mood problems

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Researchers are developing and testing drugs that may help correct the abnormal brain-cell connections that contribute to many of the intellectual and behavioral features of fragile X syndrome. One study suggested that individuals treated with one of these drugs (called fenobam) showed calmed behavior, with less anxiety and hyperactivity (10). Though these results are promising, more studies are needed on the safety and effectiveness of fenobam and related drugs.

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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, in order to develop effective treatments. Another 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. One grantee is examining language development in girls with fragile X syndrome, in order to improve diagnosis and treatment of affected girls.

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Where can a family get additional information on fragile X syndrome?

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• U.S. Centers for Disease Control and Prevention (CDC)

• The National Fragile X Foundation (800) 688-8765

• FRAXA Research Foundation (978) 462-1866

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References

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1. Centers for Disease Control and Prevention (CDC). (2006). Fragile X Syndrome. Retrieved November 9, 2009.

2. American College of Obstetricians and Gynecologists (ACOG). (2006). ACOG Committee Opinion number 338: Screening for fragile X syndrome. Washington, D.C.: Author.

3. Saul, R.A. & Tarleton, J.C. (2008). FMR1-Related Disorders. Gene Reviews. Retrieved November 9, 2009.

4. Fragile X Research Foundation. (2009). About Fragile X. Retrieved November 6, 2009.

5. Hagerman, R.J., Berry-Kravis, E., Kaufman, W.E., Ono, M.Y., Tartaglia, N. et al. (2009). Advances in the treatment of fragile X syndrome. Pediatrics, 123 (1), 378-390.

6. Verkerk. A.J.M.H., Pieretti, M., Sutcliffe, J.S., Fu, Y-H., Kuhl, D.P.A., et al. (1991). Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell, 65, 905-914.

7. Bailey, D.B., Raspa, M., Bishop, E. & Holiday, D. (2009). No change in the age of diagnosis for fragile X syndrome: Findings from a national parent survey. Pediatrics, 124 (2), 527-533.

8. McConkie-Rosell, A., Abrams, L., Finucane, B., Cronister, A., Gane, L.W., et al. (2007). Recommendations from multi-disciplinary focus groups on cascade testing and genetic counseling for fragile X-associated disorders. Journal of Genetic Counseling, 16 (5), 593-606.

9. Sherman, S., Pletcher, B.A. & Driscoll, D.A. (2005). American College of Medical Genetics Practice Guideline: Fragile X syndrome: diagnostic and carrier testing. Genetics in Medicine, 7 (8), 584-587.

10. Berry-Kravis, E.M., Hessl, D., Coffey, S., Hervey, C., Schneider, A., et al. (2009). A pilot open-label single-dose trial for fenobam in adults with fragile X syndrome. Journal of Medical Genetics, 46, 266-271.

 

April 2010