Fragile X syndrome, a genetic condition involving changes in the long arm of the X chromosome, is the most common form of inherited mental retardation. Individuals with this condition have developmental delay, variable levels of mental retardation, and behavioral and emotional difficulties. They may also have characteristic physical traits. Generally, males are affected with moderate mental retardation (since they only have one X chromosome) and females with mild mental retardation.
Description
Fragile X syndrome is the most common form of inherited mental retardation in the United States. Fragile X syndrome is caused by a mutation in the FMR-1 gene, located on the X chromosome. The FMR-1 gene is thought to play an important role in the development of the brain, but the exact way that the gene acts in the body is not fully understood. Language delays, behavioral problems, autism or autistic-like behavior (including poor eye contact and hand-flapping), enlarged genitalia (macroorchidism), large or prominent ears, hyperactivity, delayed motor development, and/or poor sensory skills are among the wide range of characteristics associated with this disorder.
Fragile X syndrome affects males and females of all ethnic groups. A summary of existing research conducted by the Centers for Disease Control and Prevention in 2001 estimated that approximately one in 3,500–8,900 males is affected by the full mutation of the FMR-1 gene and that one in 1,000 males has the premutation form of the FMR-1 gene. This study also estimated that one in 250–500 females in the general
population has the premutation. Another study estimated that one in 4,000 females is affected by the full mutation.
Causes and symptoms
For reasons not fully understood, the CGG sequence in the FMR-1 gene can expand through succeeding generations to contain between 54 and 230 repeats. This stage of expansion is called a premutation. People who carry a premutation do not usually have symptoms of fragile X syndrome, although there have been reports of individuals with a premutation who have subtle intellectual or behavioral symptoms. Individuals who carry a fragile X premutation are at risk for having children or grandchildren with the premutation. Female premutation carriers may also be at increased risk for earlier onset of menopause.
Premutation carriers may exist through several generations of a family though no symptoms of fragile X syndrome appear. However, the size of the premutation can expand over succeeding generations. When a man carries a premutation on his X chromosome, it tends to be stable and usually will not expand if he passes it on to his daughters (he passes his Y chromosome to his sons). Thus, all of his daughters will be premutation carriers like he is. When a woman carries a premutation, it is unstable and can expand as she passes it on to her children; therefore, a man's grandchildren are at greater risk of developing the syndrome. There is a 50 percent risk for a premutation carrier female for transmitting an abnormal mutation with each pregnancy. The likelihood for the premutation to expand is related to the number of repeats present; the higher the number of repeats, the greater the chance that the premutation will expand to a full mutation in the next generation. All mothers of a child with a full mutation are carriers of an FMR-1 gene expansion.
Once the size of the premutation exceeds 230 repeats, it becomes a full mutation, and the FMR-1 gene is disabled. Individuals who carry the full mutation may have fragile X syndrome. Since the FMR-1 gene is located on the X chromosome, males are more likely to develop symptoms than females. This greater inclination occurs because males have only one copy of the X chromosome. Males who inherit the full mutation are expected to have mental impairment. A female's normal X chromosome may compensate for her chromosome with the fragile X gene mutation. Females who inherit the full mutation have an approximately 30–50 percent risk of mental impairment, ranging from mild learning disability to mental retardation and behavioral problems.
Another feature of fragile X syndrome is that mosaicism is present in 15 to 20 percent of those affected by the condition. Mosaicism refers to the presence of cells of two different genetic materials in the same individual.
Individuals with fragile X syndrome appear normal at birth, but their development is delayed. Most boys with fragile X syndrome have mental impairment. The severity of mental impairment ranges from learning disabilities to severe mental retardation. Behavioral problems include attention deficit and hyperactivity at a young age. Some may show aggressive behavior in adulthood. Short attention span, poor eye contact, delayed and disordered speech and language, emotional instability, and unusual hand mannerisms (hand flapping or hand biting) are also seen frequently. Other behavioral characteristics include whirling, spinning, and occasionally autism or autistic-like behavior.
Characteristic physical traits appear later in childhood. These traits include a long and narrow face, prominent jaw, large ears, and enlarged testes. In females who carry a full mutation, the physical and behavioral features and mental retardation tend to be less severe. About 50 percent of females who have a full mutation are mentally retarded.
Children with fragile X syndrome often have frequent ear and sinus infections. Nearsightedness and lazy eye are also common. Many babies with fragile X syndrome may have trouble with sucking, and some experience digestive disorders that cause frequent gagging and vomiting. A small percentage of children with fragile X syndrome may experience seizures. Children with fragile X syndrome also tend to have loose joints, which may result in joint dislocations. Some children develop a curvature in the spine, flat feet, and a heart condition known as mitral valve prolapse.
When to call the doctor
If a child exhibits delayed development and mental impairment and has other symptoms typical of fragile X syndrome, the doctor should be consulted to determine the cause of the problems.
Diagnosis
A birth, there may be few outward signs of fragile X syndrome in the newborn infant. However, fragile X symptoms may include a large head circumference and oversized testes in males. An experienced geneticist may recognize subtle differences in facial characteristics.
However, any child with signs of developmental delay of speech, language, or motor development with
no known cause should be considered for fragile X testing, especially if there is a family history of the condition. Behavioral and developmental problems may indicate fragile X syndrome, particularly if there is a family history of mental retardation. Definitive identification of the fragile X syndrome is made by means of a genetic test to assess the number of CGG sequence repeats in the FMR-1 gene. Individuals with the premutation or full mutation may be identified through genetic testing. Genetic testing for and detection of the fragile X mutation can be performed on the developing baby before birth through amniocentesis, chorionic villus sampling (CVS), and percutaneous umbilical blood sampling. Prenatal testing is recommended after the fragile X carrier status of the parents has been confirmed, and the couple has been counseled regarding the risks of recurrence.
Prognosis
Early diagnosis and intensive intervention offer the best prognosis for individuals with fragile X syndrome. Adults with fragile X syndrome may benefit from vocational training and may need to live in a supervised setting. About 50 percent of affected individuals develop mitral valve prolapse, a heart condition, as adults. However, life span is typically normal.
KEY TERMS
Amniocentesis—A procedure performed at 16-18 weeks of pregnancy in which a needle is inserted through a woman's abdomen into her uterus to draw out a small sample of the amniotic fluid from around the baby for analysis. Either the fluid itself or cells from the fluid can be used for a variety of tests to obtain information about genetic disorders and other medical conditions in the fetus.
CGG or CGG sequence—Shorthand for the DNA sequence: cytosine-guanine-guanine. Cytosine and guanine are two of the four molecules, called nucleic acids, that make up DNA.
Chorionic villus sampling—A procedure performed at 10 to 12 weeks of pregnancy in which a needle is inserted either through the mother's vagina or abdominal wall into the placenta to withdraw a small amount of chorionic membrane from around the early embryo. The chorionic membrane can be examined for signs of chromosome abnormalities or other genetic diseases.
Chromosome—A microscopic thread-like structure found within each cell of the human body and consisting of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Chromosomes contain the genetic information necessary to direct the development and functioning of all cells and systems in the body. They pass on hereditary traits from parents to child (like eye color) and determine whether the child will be male or female.
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 brain development.
Mitral valve prolapse—A heart defect in which the mitral valve of the heart (which normally controls blood flow from the left atrium to the left ventricle) becomes floppy. Mitral valve prolapse may be detected as a heart murmur but there are usually no symptoms.
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 a person's gender. Normal males have both an X and a Y chromosome, and normal females have two X chromosomes.
Prevention
Neither the fragile X premutation nor mutation is preventable as of 2004. Genetic counseling may help prospective parents with a family history of fragile X
syndrome. Genetic testing can help determine the level of risk in the family.
Parental concerns
A child with fragile X syndrome requires many services, so parents must be prepared to invest significant time and resources to ensure the child receives the help that he or she needs.
Families may wish to seek counseling regarding the effects of the syndrome on relationships within the family. Many people respond with guilt, fear, or blame when a genetic disorder is diagnosed in the family, or they may overprotect the affected member. Support groups are often good sources of information about fragile X syndrome; they can offer helpful suggestions about living with it as well as emotional support.
BOOKS
Dew-Hughes, Denise. Educating Children with Fragile X Syndrome. New York: Falmer Press, 2004.
Fragile X Syndrome: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet Resources. San Diego, CA: Icon Health Publications, 2004.
Parker, James N., and Parker, Philip M. The 2002 Official Patient's Sourcebook on Fragile X Syndrome. San Diego, CA: Icon Health Publications, 2002.
Saunders, Suzanne. Fragile X Syndrome. New York: Taylor and Francis Group, 2001.
Weber, Jayne Dixon. Children with Fragile X Syndrome: A Parents' Guide. Bethesda, MD: Woodbine House, 2000.
ORGANIZATIONS
Arc of the United States (formerly Association for Retarded Citizens of the United States). 500 East Border St., Suite 300, Arlington, TX 76010. Web site: <http://thearc.org>.
FRAXA Research Foundation. 45 Pleasant Street, Newburyport, MA 01950. Web site: <www.fraxa.org>.
National Fragile X Foundation. PO Box 190488, San Francisco, CA 94119–0988. Web site: <www.FragileX.org>.
WEB SITES
"Families and Fragile X Syndrome." National Institute of Child Health & Human Development, National Institutes of Health. Available online at <www.nichd.nih.gov/publications/pubs/fragileX/index.htm> (accessed November 19, 2004).
