X-linked recessive inheritance
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Fragile X syndrome

Fragile X Syndrome is the most common inherited cause of mental retardation, and is associated with autism. more...

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The fragile X syndrome is a genetic disorder caused by mutation of the FMR1 gene on the X chromosome. Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 4000 females.

Normally, the FMR1 gene contains between 6 and 53 repeats of the CGG codon (trinucleotide repeats). In people with the fragile X syndrome, the FMR1 allele has over 230 repeats of this codon.

Expansion of the CGG repeating codon to such a degree results in a methylation of that portion of the DNA, effectively silencing the expression of the FMR1 protein.

This methylation of the FMR1 locus in chromosome band Xq27.3 is believed to result in constriction and fragility of the X chromosome at that point, a phenomenon that gave the syndrome its name.

The mutation and methylation of the FMR1 gene lead to the transcriptional silencing of the fragile X-mental retardation protein, FMRP. In normal individuals, FMRP binds and facilitates the translation of a number of essential neuronal RNAs. In fragile X patients, however, these RNAs are not translated into proteins. The various sequelae of fragile X syndrome result.

Transmission of the Fragile X

The diagram (above) of X-linked recessive inheritance is not entirely inappropriate but it markedly oversimplifies the situation and does not provide a sufficient foundation for genetic counseling with the fragile X syndrome.

Because males normally have only one copy of the X chromosome, those males with significant trinucleotide expansion at the FMR1 locus are symptomatic. They are mentally retarded and may show various physical features of the fragile X syndrome.

Females have two X chromosomes and thus have double the chance of having a working FMR1 allele. Females carrying one X chromosome with an expanded FMR1 gene can have some signs and symptoms of the disorder or be normal.

Males with the fragile X cannot transmit it to any of their sons (since males contribute a Y chromosome, not an X, to their male offspring.)

Females carrying one copy of the fragile X can transmit it to their sons or daughters. Sons who receive the fragile X are at high risk for mental retardation. Daughters who receive the fragile X may appear normal or they may be mentally retarded, usually to a lesser degree than boys with the syndrome.


Aside from mental retardation, prominent characteristics of the syndrome include an elongated face, large or protruding ears, large testicles (macroorchidism), and low muscle tone. Behavioral characteristics may include stereotypic movements (e.g., hand-flapping) and atypical social development, particularly shyness and limited eye contact. Some individuals with the fragile X syndrome also meet the diagnostic criteria for autism.

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Fragile X syndrome
From Gale Encyclopedia of Medicine, 4/6/01 by Julia Barrett


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.


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.


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.


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.


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.


Neither the premutation nor the mutation is preventable.

Key Terms

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.
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.
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


  • 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.


  • 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.


  • 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.

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