Fragile X Syndrome

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Definition

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.

Description

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 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.

— Nada Quercia, MS, CCGC

An inherited disorder caused by a defective gene on the X-chromosome and causing mental retardation, enlarged testes, and facial abnormalities in males and mild or no effects in heterozygous females. It is the most common inherited cause of mental retardation.

Definition

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 is also known as Martin-Bell syndrome, Marker X syndrome, and FRAXA syndrome.

Demographics

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.

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.

Resources

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: .

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).

[Article by: Judith Sims, MS Nada Quercia, MS, CCGC]

Fragile X syndrome is one of the most common causes of inherited mental retardation. Individuals with fragile X syndrome can exhibit moderate to severe mental retardation. Additional characteristics may include autistic-like behavior, hyperactivity, mitral valve prolapse (a heart valve defect), a large head circumference, a long face with a prominent forehead and jaw, protruding ears, flat feet, hyper-extensive joints ("double-jointedness"), and, in males, enlarged testicles. Fragile X syndrome is not restricted to any ethnic group. It was the first of the so-called triplet repeat diseases to be discovered, and study of it has led to a growing understanding of DNA instability and its role in disease.

Discovery of the Syndrome

The first family with fragile X syndrome was described by J. Purdon Martin and Julia Bell in 1943. This family had eleven severely retarded males, and the inheritance pattern of the mental retardation appeared to be X-linked. X-linked traits are inherited on the X chromosome and are more common in males, who have only one X chromosome, than in females, who have two.

In 1969, in a different family, Herbert Lubs observed a constriction near the end of the long, or q, arm of the X chromosome in four mentally retarded males and two of their mentally normal female relatives. This constriction made the X chromosome appear to be broken. Hence the name "fragile X."

For years, little attention was paid to Lubs's finding. Renewed interest in the observation emerged in the late 1970s, when additional families were identified with mental retardation and the same chromosome abnormality, or fragile site. Moreover, in 1977 Grant Sutherland discovered that the ability to detect this fragile site was dependent on the chemicals used to study patients' chromosomes. Sutherland's crucial observation helped develop the first diagnostic test for fragile X syndrome. Using this knowledge, investigators reexamined chromosomes from the original fragile X family described in 1943 and demonstrated that, indeed, affected individuals in this family carried the characteristic fragile site.

Puzzling Inheritance Pattern

While the location of this fragile site established that fragile X syndrome was indeed X-linked, inheritance of this disorder was clearly not typical of other X-linked disorders. At first, it was believed that fragile X syndrome was an X-linked recessive genetic disorder. However, there were many observations inconsistent with this inheritance pattern.

If the disorder was truly inherited in an X-linked recessive manner, heterozygote carrier women would not display any characteristics of the syndrome, and all carrier males would. But there were reports of affected females, and of males who carried the fragile site but were unaffected. It was particularly difficult to reconcile that some male carriers could be so severely affected while others were completely unaffected.

Because of these puzzling observations, in 1985 Stephanie Sherman and her colleagues studied the inheritance pattern of fragile X syndrome more closely. They demonstrated that the risk of expressing mental retardation was dependent on the individual's position in the pedigree, with risk increasing in later generations. The daughter of an unaffected male carrier was more likely to have affected offspring than the mother of the unaffected male carrier was: something had changed on the X chromosome over the two generations. This observation became known as the "Sherman paradox" and was crucial to understanding the genetic mutation that causes fragile X syndrome.

To explain the unusual inheritance pattern, Sherman, her colleagues, and several other scientists hypothesized that the alleged gene for fragile X syndrome was mutated in a two-step process. They proposed that the first mutation caused a "premutation" state that produced no clinical symptoms, and that a second mutation was required to convert the premutation to a "full mutation" form that was associated with the characteristic symptoms of fragile X syndrome. Moreover, conversion from a premutation to a full mutation was proposed to occur only when the premutation was transmitted from a carrier female.

An Expanding Gene

In 1991 an international team of scientists identified the gene and mutation that causes fragile X syndrome. They found that in families with fragile X syndrome, there is a piece of the FMR1 gene, called a CGG repeat, which is abnormally expanded.

In the general population, the repeat length can range from about six to fifty-four copies of the CGG, and the repeat is stable, or is passed from parent to child without change. In fragile X families, the premutation form of the repeat contains between fifty and two hundred copies of the CGG repeat, and the repeat is unstable.

Premutation alleles can expand to full mutation alleles (with more than two hundred copies of the CGG repeat) by transmission of the premutation from a mother to her child. A woman's risk of having a child with the full mutation correlates to her own repeat size. The larger her premutation, the more she risks having a child who carries the full mutation.

The CGG repeat is usually interrupted by a single AGG trinucleotide every ten CGG repeats, but this can vary from individual to individual. Because premutation alleles have fewer AGG interruptions compared with normal-size FMR1 alleles, it is believed that the AGG interruptions are important for stability of the CGG repeat.

Individuals with a premutation do not express the clinical symptoms associated with fragile X syndrome, although it has been reported that pre-mutation carrier females can experience premature ovarian failure. Individuals who carry the full mutation can express symptoms of fragile X syndrome because they are missing the protein produced by the FMR1 gene. Males with a full mutation always exhibit some symptoms of the disorder. Due to X inactivation, females with a full mutation may or may not express symptoms.

Although there is currently no cure for fragile X syndrome, scientists are making great progress in understanding the biology of the disorder. In the mid-to late 1990s, Stephen Warren and colleagues determined that the FMR1 gene product, named FMRP, is an RNA-binding protein that shuttles in and out of the nucleus and is involved in binding various messenger RNAs. Moreover, scientists successfully developed mice that lack the FMR1 gene, which will greatly aid research. Symptoms of fragile X mice include learning disabilities, hyperactivity, and, in males, enlarged testicles. Prevailing hypotheses about FMRP suggest that this protein is involved in forming neural connections in the developing brain.

The identification of FMR1 and the expanded CGG repeats was a landmark discovery in human genetics because it established a novel class of human genetic mutations, trinucleotide (or triplet) repeat expansions. Since the discovery of FMR1 and the expanding CGG repeats, scientists have identified more than ten other human genetic disorders that are caused by expansions of trinucleotide repeats, including disorders such as Huntington's disease and myotonic muscular dystrophy.

Bibliography

Hagerman, Randi Jenssen, and Amy Cronister, eds. Fragile X Syndrome: Diagnosis, Treatment, and Research, 2nd ed. Baltimore: Johns Hopkins University Press, 1996.

Internet Resource

Online Mendelian Inheritance in Man: Fragile Site Mental Retardation 1; FMR1. JohnsHopkins University and National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?309550.

—Allison Ashley-Koch

Fragile X syndrome
Classification & external resources

Location of FMR1 gene
ICD-10	Q99.2
ICD-9	759.83
OMIM	309550
DiseasesDB	4973
eMedicine	ped/800
MeSH	D005600

Fragile X syndrome is a syndrome of X-linked mental retardation. Boys with the syndrome may have large testicles (macroorchidism), prognathism, hypotonia and autism, and a characteristic but variable face with large ears, long face, high-arched palate, gynecomastia, and malocclusion. Additional abnormalities may include lordosis, heart defect, pectus excavatum, flat feet, shortening of the tubular bones of the hands, and joint laxity. Females who have one fragile chromosome and one normal X chromosome may range from normal to mild manifestations of the fragile X syndrome. The fragile X syndrome has an estimated incidence of 1 in 3600 males and 1 in 4,000–6,000 females. ^[1]

History

Martin and Bell in 1943, described a pedigree of X-linked mental disability, without considering the macroorchidism.^[2] In 1969 Herbert Lubs first sighted an unusual "marker X chromosome" in association with mental disability.^[3] In 1970 Frederick Hecht coined the term "fragile site" (Renpenning's syndrome is not synonymous with the Martin-Bell (fragile X) syndrome). In Renpennig's syndrome there is no fragile site on the X chromosome. Renpenning’s cases had short stature, moderate microcephaly, and neurological disorders.

Escalante's syndrome is synonymous with the fragile X syndrome. This term has been used in Brazil and other South American countries.

Causes

X-linked recessive inheritance

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 259 females. (Incidence of the disease itself is about 1 in every 4000 females.)

Normally, the FMR1 gene contains between 6 and 55 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 of the X chromosome which appears 'fragile' under the microscope at that point, a phenomenon that gave the syndrome its name.

Mutation of the FMR1 gene leads 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.

Transmission of the Fragile X

The diagram (right) 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 about the fragile X syndrome. Technically, fragile X syndrome is an X-linked dominant condition with reduced penetrance.

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 intellectually disabled 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. Although the extra X chromosome can serve as a backup, only one X chromosome is active at a time due to X-inactivation.

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), but will transmit it to all of their daughters, as males contribute their X to all of their daughters.

Females carrying one copy of the fragile X can transmit it to their sons or daughters; in this case each child has a 50% chance of inheriting the fragile X. Sons who receive the fragile X are at high risk of intellectual disability. Daughters who receive the fragile X may appear normal or they may be intellectually disabled, usually to a lesser degree than boys with the syndrome. The transmission of fragile X often increases with each passing generation. This seemingly anomalous pattern of inheritance is referred to as the Sherman paradox.

Symptoms

Prominent characteristics of the syndrome include an elongated face, large or protruding ears, and low muscle tone.

Aside from intellectual disability, prominent characteristics of the syndrome include an elongated face, large or protruding ears, flat feet, larger testicles in men (macroorchidism), and low muscle tone. Speech may include cluttered speech or nervous speech^[4]. 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. Most females experience symptoms to a lesser degree because of their second X-chromosome, however they can develop just as severe symptoms. While full mutation males tend to present with severe intellectual disability, the symptoms of full mutation females runs the gamut of minimally affected to severe intellectual disability, which may explain why females are underdiagnosed relative to males.

Diagnosis

Fragile X syndrome was originally diagnosed by culturing cells in a folate deficient medium and then assessing the cultures for X-chromosome breakage by cytogenetic analysis of the long arm of the X chromosome. This technique proved unreliable for both diagnosis and carrier testing.

The fragile X abnormality is now directly determined by analysis of the number of CGG repeats and their methylation status using restriction endonuclease digestion and Southern blot analysis.

Treatment and current research

Recent studies have focused on a number of critical areas. The role of FMRP's RNA partners, many of which have now been validated through in vitro assays, is of primary importance. Also being examined is the function the various domains of FMRP, an RNA-binding protein, which is still relatively unknown.

While there is no current cure for the syndrome, there is hope that further understanding of its underlying causes would lead to new therapies. Currently, the syndrome can be treated through behavioral therapy, special education, medication, and when necessary, treatment of physical abnormalities. Persons with the fragile X syndrome in their family histories are advised to seek genetic counseling to assess the likelihood of having children who are affected, and how severe any impairments may be in affected descendants.

Researchers at the Picower Institute for Learning and Memory at MIT have reversed symptoms of mental retardation and autism in mice.^[5]

References

1. ^ Crawford, D.C.; Acuna, J.M. & Sherman, S.L. (2001) "FMR1 and the Fragile X syndrome: Human genome epidemiology review". Genet Med 3: 359-371
2. ^ Martin, J. P. & Bell, J. "A pedigree of mental defect showing sex-linkage". Journal of neurology, neurosurgery, and psychiatry (J. Neurol. Psychiat.). BMJ Publishing Group, London 6.1943, 154-157. ISSN 0022-3050
3. ^ Lubs, H. (1969) "A marker X chromosome". Am Hum Genet 21: 231.
4. ^ http://www.wrongdiagnosis.com/f/fragile_x_syndrome/signs.htm
5. ^ MIT researchers reverse symptoms in mice of leading inherited cause of mental retardation

External links

• CDC’s National Center on Birth Defects and Developmental Disabilities
• FraXA.org - The Fragile X Research Foundation
• http://www.fragilex.org.uk/index.asp - The United Kingdom National Fragile X charity
• FragileX.org - The National Fragile X Foundation (US) - Support, Awareness, Education, Research and Advocacy since 1984
• The Colorado Fragile X Consortium
• Stanford.edu - 'Trinucleotide Repeat Disorders Part 9: Non-Polyglutamine Diseases: Descriptions of other diseases that involve codon repeat expansions' (September 18, 2002)
• Genetics of Fragile X Syndrome
• Gene Reviews

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