Fragile X syndrome

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

 

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

  • 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

 

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):

  • Learning disabilities involving math
  • Attention difficulties
  • Speech delays
  • Emotional problems, such as anxiety, depression and shyness
  • Poor social skills

 

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.

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).

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.

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).

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 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.

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).

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.

     

    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.

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).

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

 

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):

  • Physical or behavioral signs and symptoms of fragile X syndrome
  • A family history of fragile X syndrome or intellectual disabilities of unknown cause

 

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:

  • 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

 

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.

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.

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.

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:

  • 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

 

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.

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.

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

 

References

  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

Most common questions

Can dad's exposure to chemicals harm his future kids?

Dad's exposure to harmful chemicals and substances before conception or during his partner's pregnancy can affect his children. Harmful exposures can include drugs (prescription, over-the-counter and illegal drugs), alcohol, cigarettes, cigarette smoke, chemotherapy and radiation. They also include exposure to lead, mercury and pesticides.

Unlike mom's exposures, dad's exposures do not appear to cause birth defects. They can, however, damage a man's sperm quality, causing fertility problems and miscarriage. Some exposures may cause genetic changes in sperm that may increase the risk of childhood cancer. Cancer treatments, like chemotherapy and radiation, can seriously alter sperm, at least for a few months post treatment. Some men choose to bank their sperm to preserve its integrity before they receive treatment. If you have a question about a specific exposure, contact the Organization of Teratology Information Specialists at www.otispregnancy.org.

Can Rh factor affect my baby?

The Rh factor may be a problem if mom is Rh-negative but dad is Rh-positive. If dad is Rh-negative, there is no risk.

If your baby gets her Rh-positive factor from dad, your body may believe that your baby's red blood cells are foreign elements attacking you. Your body may make antibodies to fight them. This is called sensitization.

If you're Rh-negative, you can get shots of Rh immune globulin (RhIg) to stop your body from attacking your baby. It's best to get these shots at 28 weeks of pregnancy and again within 72 hours of giving birth if a blood test shows that your baby is Rh-positive. You won't need anymore shots after giving birth if your baby is Rh-negative. You should also get a shot after certain pregnancy exams like an amniocentesis, a chorionic villus sampling or an external cephalic version (when your provider tries to turn a breech-position baby head down before labor). You'll also want to get the shot if you have a miscarriage, an ectopic pregnancy or suffer abdominal trauma.

Does cleft lip or cleft palate cause dental problems?

A cleft lip or cleft palate that extends into the upper gums (where top teeth develop) can cause your baby to have certain dental problems, including:

  • Missing teeth
  • Too many teeth
  • Oddly shaped teeth
  • Teeth that are out of position around the cleft

Every baby with a cleft lip or palate should get regular dental checkups by a dentist with experience taking care of children with oral clefts. Dental problems caused by cleft lip or palate usually can be fixed. If needed, your baby can get ongoing care by a team of experts, including:

  • A dentist
  • An orthodontist to move teeth using braces
  • An oral surgeon to reposition parts of the upper jaw, if needed, and to fix the cleft

See also: Cleft lip and cleft palate

 

Does cleft lip or cleft palate cause ear problems?

Cleft lip does not cause ear problems.

Babies with cleft palate, however, are more likely than other babies to have ear infections and, in some cases, hearing loss. This is because cleft palate can cause fluid to build up in your baby’s middle ear. The fluid can become infected and cause fever and earache. If fluid keeps building up with or without infection, it can cause mild to moderate hearing loss.

Without treatment , hearing loss can affect your baby’s language development and may become permanent.

With the right care, this kind of hearing loss is usually temporary. Your baby’s provider may recommend:

  • Having your baby’s ears checked regularly for fluid buildup
  • Medicines for treating fluid buildup and ear infections
  • Ear tubes if your baby has fluid in his ears over and over again. Ear tubes are tiny tubes that are inserted into the eardrum to drain the fluid and help prevent infections.

See also: Cleft lip and cleft palate

Does cleft lip or cleft palate cause problems with breastfeeding?

Babies with only a cleft lip usually don’t have trouble breastfeeding. Most of the time, they can breastfeed just fine. But they may need some extra time to get started.

Babies with cleft lip and palate or with isolated cleft palate can have:

  • Trouble sucking strong enough to draw milk through a nipple
  • Problems with gagging or choking
  • Problems with milk coming through the nose while feeding

Most babies with cleft palate can’t feed from the breast. If your baby has cleft palate, he can still get the health benefits of breastfeeding if you feed him breast milk from a bottle. Your provider can show you how to express (pump) milk from your breasts and store breast milk.

Your baby’s provider can help you start good breastfeeding habits right after your baby is born. She may recommend:

  • Special nipples and bottles that can make feeding breast milk from a bottle easier
  • An obturator. This is a small plastic plate that fits into the roof of your baby’s mouth and covers the cleft opening during feeding.

See also: Cleft lip and cleft palate, Breastfeeding

Does cleft lip or cleft palate cause speech problems?

Children with cleft lip generally have normal speech. Children with cleft lip and palate or isolated cleft palate may:

  • Develop speech more slowly
  • Have a nasal sound when speaking
  • Have trouble making certain sounds

Most children can develop normal speech after having cleft palate repair. However, some children may need speech therapy to help develop normal speech.

See also: Cleft lip and cleft palate

What are choroid plexus cysts?

The choroid plexus is the area of the brain that produces the fluid that surrounds the brain and spinal cord. This is not an area of the brain that involves learning or thinking. Occasionally, one or more cysts can form in the choroid plexus. These cysts are made of blood vessels and tissue. They do not cause intellectual disabilities or learning problems. Using ultrasound, a health care provider can see these cysts in about 1 in 120 pregnancies at 15 to 20 weeks gestation. Most disappear during pregnancy or within several months after birth and are no risk to the baby. They aren't a problem by themselves. But if screening tests show other signs of risk, they may indicate a possible genetic defect. In this case, testing with higher-level ultrasound and/or amniocentesis may be recommended to confirm or rule out serious problems.

What if I didn't take folic acid before pregnancy?

If you didn’t take folic acid before getting pregnant, it doesn't necessarily mean that your baby will be born with birth defects. If women of childbearing age take 400 micrograms of folic acid every day before and during early pregnancy, it may help reduce their baby’s risk for birth defects of the brain and spin called neural tube defects (NTDs). But it only works if you take it before getting pregnant and during the first few weeks of pregnancy, often before you may even know you’re pregnant.

Because nearly half of all pregnancies in the United States are unplanned, it's important that all women of childbearing age (even if they're not trying to get pregnant) get at least 400 micrograms of folic acid every day. Take a multivitamin with folic acid before pregnancy. During pregnancy, switch to a prenatal vitamin, which should have 600 micrograms of folic acid.

Last reviewed November 2012

©2013 March of Dimes Foundation. The March of Dimes is a non-profit organization recognized as tax-exempt under Internal Revenue Code section 501(c)(3).