Fragile X syndrome

Definition

Fragile X syndrome is caused by a mutated gene on the X chromosome. Affected individuals have developmental delays, variable levels of mental retardation, and behavioral and emotional problems. They may also have characteristic physical traits. Males are affected more severely than females.

Description

Fragile X syndrome is the most common form of inherited mental retardation. Estimates of the incidence of this syndrome vary, but it is thought to affect about one in 2,000 girls and one in 1,250 boys. The syndrome is caused by a mutation in the FMR-1 gene, located on the X chromosome. The role of the gene is unclear, but it is probably important in early development.

The mutation involves a short sequence of DNA in the gene. This sequence is designated CGG. Normally, there are fewer than 50 adjacent copies of the CGG sequence. If the CGG sequence repeats more than 200 times, the FMR-1 gene is disabled.

The inheritance pattern of fragile X syndrome is complex. A condition called premutation may exist through several generations of a family, and no symptoms of fragile X will appear. During this premutation phase, the CGG sequence repeats 50-200 times. The size of the premutation expands over succeeding generations. Once the premutation reaches more than 200 repetitions, it becomes a full mutation. Individuals who have the full mutation may have fragile X syndrome.

Causes & symptoms

Fragile X syndrome is caused by a full mutation in the FMR-1 gene on the X chromosome. Because boys have just one copy of the X chromosome, they are more likely to develop symptoms than girls are. Fragile X boys appear normal at birth but development is delayed and they may have behavioral problems as they get older. Common behavioral problems include hyperactivity and attention problems known as attention deficit disorder. Approximately 90% of fragile X boys are mentally retarded, although the severity of the retardation varies. Characteristic physical traits appear later in childhood. These traits include enlarged testes, prominent ears, and a long, narrow face.

A girl's normal X chromosome may compensate for her fragile X chromosome. Approximately 30-50% of girls with a full mutation develop symptoms. These symptoms include mental impairment, ranging from mild learning disability to mental retardation, and behavioral problems. Characteristic physical traits are less noticeable in girls than in boys. Girls may not have these traits at all.

Children with fragile X syndrome often have frequent ear and sinus infections. Nearsightedness and lazy eye are also common. Many children experience digestive disorders that cause frequent gagging, vomiting, and discomfort. A small percentage may also experience seizures.

Diagnosis

Behavioral and developmental problems may indicate fragile X syndrome, particularly if there is a family history of mental retardation. Definitive identification is made by means of a genetic test for the mutation. Individuals with the premutation or mutation may also be identified through genetic testing. Amniocentesis, chorionic villus sampling, and percutaneous umbilical blood sampling can be used to identify a fragile X chromosome before birth.

Treatment

Fragile X syndrome cannot be cured. To reach his or her full potential, a child may require speech and language therapy, occupational therapy, and physical therapy. The expertise of psychologists, special education teachers, and genetic counselors may also be needed. Drugs are used to treat hyperactivity, seizures, and other problems. Establishing a regular routine, avoiding over stimulation, and using calming techniques can help reduce behavioral problems.

Prognosis

Early diagnosis and intensive intervention offer the best prognosis for fragile X individuals. They can learn and are often good at memorizing and imitation. Most behavioral problems decrease by adulthood. About 50% of fragile X individuals develop mitral valve prolapse, a heart condition, as adults. Life span is typically normal.

Prevention

Neither the premutation nor the mutation is preventable.

Key Terms

Amniocentesis

A procedure in which a needle is inserted through a pregnant woman's abdomen and into her uterus to withdraw a small sample of the fluid that surrounds the fetus (amniotic fluid). The amniotic fluid can be examined for signs of disease or other problems afflicting the fetus.

CGG or CGG sequence

Shorthand for the DNA sequence: cytosine-guanine-guanine. Cytosine and guanine are two of the four molecules, otherwise called nucleic acids, that make up DNA.

Chorionic villus sampling

A medical procedure done during weeks 10-12 of a pregnancy. A needle is inserted into the placenta and a small amount fetal tissue is withdrawn for analysis.

Chromosome

A structure made of DNA and contained within a cell's nucleus. The DNA condenses into these readily recognizable structures only at certain times during cell growth. In humans, DNA is bundled into 23 pairs of chromosomes, each of which has recognizable characteristics, such as length and staining patterns, that allow individual chromosomes to be identified. Identification is assigned by number (1-22) or letter (X or Y).

FMR-1 gene

A gene found on the X chromosome. Its exact purpose is unknown, but it is suspected that the gene plays a role in development.

Percutaneous umbilical blood sampling

In this procedure, also known as cordocentesis, a needle is inserted through the skin of a pregnant woman into the a blood vessel in the umbilical cord to obtain a sample of fetal blood for testing.

Premutation

A change in a gene that precedes a mutation; this change does not alter the function of the gene.

X chromosome

One of the two sex chromosomes (the other is Y) that determine an individual's gender. Barring chromosomal defect, all individuals carry two sex chromosomes. Males have both an X and a Y chromosome, and females have two X chromosomes.

Further Reading

For Your Information

Books

• Hagerman, Randi Jenssen, and Amy Cronister, eds. Fragile X Syndrome: Diagnosis, Treatment, and Research. Baltimore: Johns Hopkins University Press, 1996.
• Nussbaum, Robert L., and David H. Ledbetter. "The Fragile X Syndrome." In The Metabolic and Molecular Bases of Inherited Disease, 7th ed., edited by Charles R. Scriver, et al. New York: McGraw-Hill, Inc., 1995.

  Periodicals

• Hagerman, Randi Jenssen. "Fragile X Syndrome: Molecular and Clinical Insights and Treatment Issues." Western Journal of Medicine, 166 (February 1997): 129-137.
• Hoogeveen, A. T., and B. A. Oostra. "The Fragile X Syndrome." Journal of Inherited Metabolic Diseases, 20 (1997): 139-151.

  Organizations

• The Arc. 500 East Border St., Suite 300, Arlington, TX 76010. (817) 261-6003. http://thearc.org/.
• National Fragile X Foundation. 1441 York St., Suite 303, Denver, CO 80206. (303) 333-6155 (in Colorado) or (800) 688-8765.
• National Fragile X Syndrome Support Group. 206 Sherman Rd., Glenview, IL 60025. (708) 724-8626.

Gale Encyclopedia of Medicine. Gale Research, 1999.