fragile X syndrome

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Fragile X Syndrome



Fragile X syndrome 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 and females with mild mental retardation.


Fragile X syndrome is also known as Martin-Bell syndrome, Marker X syndrome, and FRAXA syndrome. It is the most common form of inherited mental retardation. Fragile X 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.
In order to understand fragile X syndrome it is important to understand how human genes and chromosomes influence this condition. Normally, each cell in the body contains 46 (23 pairs of) chromosomes. These chromosomes consist of genetic material (DNA) needed for the production of proteins, which lead to growth, development, and physical/intellectual characteristics. The first 22 pairs of chromosomes are the same in males and females. The remaining two chromosomes are called the sex chromosomes (X and Y). The sex chromosomes determine whether a person is male or female. Males have only one X chromosome, which is inherited from the mother at conception, and they receive a Y chromosome from the father. Females inherit two X chromosomes, one from each parent. Fragile X syndrome is caused by a mutation in a gene called FMR-1. This gene is 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.
Fragile X syndrome affects males and females of all ethnic groups. It is estimated that there are about one in 4,000 to one in 6,250 males affected with fragile X syndrome. There are approximately one-half as many females with fragile X syndrome as there are males. The carrier frequency in unaffected females is one in 100 to one in 600, with one study finding a carrier frequency of one in 250.

Causes and symptoms

For reasons not fully understood, the CGG sequence in the FMR-1 gene can expand 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 and subtle intellectual or behavioral symptoms. Individuals who carry a fragile X premutation are at risk to have children or grandchildren with the condition. Female premutation carriers may also be at increased risk for earlier onset of menopause; however, premutation carriers may exist through several generations of a family and no symptoms of fragile X syndrome will appear.
The size of the premutation can expand over succeeding generations. 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 is 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 50% risk of mental impairment. The phenomenon of an expanding trinucleotide repeat in successive generations is called anticipation. Another unique aspect of fragile X syndrome is that mosaicism is present in 15-20% those affected by the condition. Mosaicism is when there is the presence of cells of two different genetic materials in the same individual.
The mutation involves a short sequence of DNA in the FMR-1 gene. This sequence is designated CGG. Normally, the CGG sequence is repeated between six to 54 times. People who have repeats in this range do not have fragile X syndrome and are not at increased risk to have children with fragile X syndrome. Those affected by fragile X syndrome have expanded CGG repeats (over 200) in the first exon of the FMR1 gene (the full mutation)
Fragile X syndrome is inherited in an X-linked dominant manner (characters are transmitted by genes on the X chromosome). 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% risk for a premutation carrier female to transmit 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. Ninety-nine percent of patients with fragile X syndrome have a CGG expansion, and less than one percent have a point mutation or deletion on the FMR1 gene.
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. 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% of females who have a full mutation are mentally retarded. Other behavioral characteristics include whirling, spinning, and occasionally autism.
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.


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 the fragile X mutation can be done on the developing baby before birth through amniocentesis or chorionic villus sampling (CVS), and is 99% effective in detecting the condition due to trinucleotide repeat expansion. Prenatal testing should only be undertaken after the fragile X carrier status of the parents has been confirmed and the couple has been counseled regarding the risks of recurrence. While prenatal testing is possible to do with CVS, the results can be difficult to interpret and additional testing may be required.


Presently there is no cure for fragile X syndrome. Management includes such approaches as speech therapy, occupational therapy, and physical therapy. The expertise of psychologists, special education teachers, and genetic counselors may also be beneficial. Drugs may be used to treat hyperactivity, seizures, and other problems. Establishing a regular routine, avoiding over-stimulation, and using calming techniques may also help in the management of behavioral problems. Children with a troubled heart valve may need to see a heart specialist and take medications before surgery or dental procedures. Children with frequent ear and sinus infections may need to take medications or have special tubes placed in their ears to drain excess fluid. Mainstreaming of children with fragile X syndrome into regular classrooms is encouraged because they do well imitating behavior. Peer tutoring and positive reinforcement are also encouraged.


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. 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. 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, otherwise called nucleic acids, that make up DNA.
Chorionic villus sampling (CVS) — A procedure used for prenatal diagnosis at 10-12 weeks gestation. Under ultrasound guidance a needle is inserted either through the mother's vagina or abdominal wall and a sample of cells is collected from around the early embryo. These cells are then tested for chromosome abnormalities or other genetic diseases.
Chromosome — A microscopic thread-like structure found within each cell of the body that consists of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Changes in either the total number of chromosomes or their shape and size (structure) may lead to physical or mental abnormalities.
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 one of the valves of the heart (which normally controls blood flow) 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) containing genetic material that, among other things, determine a person's gender.
A 2004 study found that men who are carriers of the fragile X gene but have not have the mutation severe enough to have fragile X syndrome may begin to show signs of tremor disorder, gait instability and memory impairment as they age. The higher prevalence of these symptoms among grandfathers of children with fragile x syndrome was noted so a study was done to investigate their symptoms compared to men of the same age without the mutation. About 17% of the grandfathers in their 50s had the condition, 37% of those in their 60s, 47% of men in their 70s and 75% of men in their 80s. Often, these men have been diagnosed with other diseases such as Parkinson's or Alzheimer's rather than with fragile X-associated tremor/ataxia syndrome, the name which has been given to these late symptoms from the fragile x mutation.



Kaufmann, Walter E., and Allan L. Reiss. "Molecular and Cellular Genetics of Fragile X Syndrome." American Journal of Medical Genetics 88 (1999): 11-24.
Kirn, Timothy F. "New Fragile X Often Misdiagnosed as Parkinson's." Clinical Psychiatry News March 2004: 84.


Arc of the United States (formerly Association for Retarded Citizens of the US). 500 East Border St., Suite 300, Arlington, TX 76010. (817) 261-6003.
National Fragile X Foundation. PO Box 190488, San Francisco, CA 94119-0988. (800) 688-8765 or (510) 763-6030. Fax: (510) 763-6223.
National Fragile X Syndrome Support Group. 206 Sherman Rd., Glenview, IL 60025. (708) 724-8626.


"Fragile X Site Mental Retardation 1; FMR1." Online Mendelian Inheritance in Man. March 6, 2001.
Tarleton, Jack, and Robert A. Saul. "Fragile X Syndrome." GeneClinics March 6, 2001.
Gale Encyclopedia of Medicine. Copyright 2008 The Gale Group, Inc. All rights reserved.

fragile X syndrome

an X-linked recessive syndrome consisting of mental retardation, a characteristic facies, and macroorchidism. DNA analysis shows abnormal trinucleotide repeats on the X chromosome near the end of its long arm, at Xq27.3. Constriction is demonstrable at this site on karyotyping after culture in folate-deficient medium.
See also: Renpenning syndrome.
Farlex Partner Medical Dictionary © Farlex 2012

fragile X syndrome

An inherited disorder caused by a defective gene on the X chromosome and marked by intellectual disability, developmental disorders, enlarged testes, and facial abnormalities in males and by mild or no effects in heterozygous females.
The American Heritage® Medical Dictionary Copyright © 2007, 2004 by Houghton Mifflin Company. Published by Houghton Mifflin Company. All rights reserved.

fragile X syndrome

Molecular oncology A condition that is the most common–1:1500 cause of inherited mental deficiency in ♂–30% of ♀ carriers are also mentally deficient Clinical Moderate mental retardation, neuropsychiatric disorders–hypotonic or hyperactive state, autism, large forehead, macroorchidism, enlarged chin, jaw, ears. Cf CAG repeat disease.
McGraw-Hill Concise Dictionary of Modern Medicine. © 2002 by The McGraw-Hill Companies, Inc.

fra·gile X syn·drome

(fraj'il sin'drōm)
The chromosomal disorder has a sex-linked recessive character. Patients have a mutation in the FMR1 gene in the manufacture of the protein fMRP; most common cause of inherited mental impairment (findings include mild-to-severe learning disabilities and autism).
Synonym(s): FMR1, marker X syndrome, Martin-Bell syndrome.
Medical Dictionary for the Health Professions and Nursing © Farlex 2012

fragile X syndrome

A major genetic disorder caused by a constriction near the end of the long arm of an X chromosome that leads to breakage or deletion. The fragile X syndrome is second only to DOWN'S SYNDROME as a cause of mental defect. Affected men have unusually high foreheads, unbalanced faces, large jaws, long protruding ears and large testicles. They have an IQ below 50 and are prone to violent outbursts. Folic acid helps to control their behaviour. About one-third of the females with this mutation on one of their two X chromosomes are also mentally retarded. Screening for the characteristic chromosome can be done by AMNIOCENTESIS or CHORIONIC VILLUS SAMPLING.
Collins Dictionary of Medicine © Robert M. Youngson 2004, 2005


J. Purdon, 20th century English physician.
Martin-Bell syndrome - Synonym(s): fragile X syndrome
Medical Eponyms © Farlex 2012

fra·gile X syn·drome

(fraj'il sin'drōm)
Syndrome consisting of mental retardation, characteristic facies, and macroorchidism.
Medical Dictionary for the Dental Professions © Farlex 2012