Fragile X Syndrome

Fragile X Syndrome

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Fragile X Syndrome is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • fragile site, folic acid type, rare, Fra(X)(Q27.3)
  • fragile X mental retardation protein, FMRP
  • fragile X mental retardation syndrome
  • marker X syndrome
  • Martin-Bell syndrome
  • mental retardation, X-linked, associated with Mar Xq28
  • X-linked mental retardation and macroorchidism

Disorder Subdivisions

  • None

General Discussion

Fragile X syndrome is characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females. Distinctive physical features are sometimes present in affected males including a large head, long face, prominent forehead and chin, protruding ears, loose joints and large testes, but these features develop over time and may not be obvious until puberty. Motor and language delays are usually present but also become more apparent over time. Behavioral abnormalities including autistic behaviors are common.



Fragile X syndrome is caused by an abnormality (mutation) in the FMR1 gene. Affected individuals have an increased number of copies of a portion of the gene called CGG repeats. The greater the number of copies of CGG, the more likely there will be increased severity of the disorder. Fragile X syndrome occurs more often in males and results in more severe disease in males.



Mutations in the FMR1 gene are associated with two other conditions in addition to the fragile X syndrome (FXTAS and POI) and these conditions have been termed FMR1-Related Disorders. (See the Related Disorders section of this report for brief summaries of the other disorders.)

Symptoms

Fragile X syndrome is characterized by moderate intellectual disability in affected males and mild intellectual disability in affected females. The physical features in affected males are variable and may not be obvious until puberty. These symptoms can include a large head, long face, prominent forehead and chin, protruding ears, loose joints and large testes. Other symptoms can include flat feet, frequent ear infections, low muscle tone, a long narrow face, high arched palate, dental problems, crossed eyes (strabismus) and heart problems including mitral valve prolapse. Delayed motor development, hyperactivity, behavior problems, toe walking, and/or occasional seizures can also occur in some patients. Autistic behaviors such as poor eye contact, hand flapping, and/or self-stimulating behaviors are also common. Motor and language delays are usually present but become more apparent over time.

Causes

Fragile X syndrome is caused by a mutation in the FMR1 gene located on the X chromosome at Xq27.3. Affected individuals have an increased number of copies of a portion of this gene called CGG. The number of CGG repeats can increase from one generation to the next. The greater the number of copies of CGG, the more likely there will be increased severity of the disorder. Too many CGG repeats triggers a process called methylation that prevents the FMR1 gene from producing the FMR protein. The FMR protein is involved in making connections between neurons (nerve cells) in the brain. The absence of this protein leads t the symptoms of fragile X syndrome.



Normal FMR1 genes have approximately 5-40 CGG repeats and this number remains stable from generation to generation. Individuals with fragile X syndrome have a full mutation of the FMR1 gene which means that they have over 200 CGG repeats. Females with a premutation of the FMR1 gene have about 50-2000 CGG repeats and are at risk to have children with fragile X syndrome because the number of CGG repeats can increase when the gene is passed into the next generation



Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome Xq27.3" refers to band 27.3 on the long arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.



X-linked dominant disorders are caused by an abnormal gene located on the X chromosome. Females with the abnormal gene may be affected by this disorder. Males are usually more severely affected than females.

Affected Populations

It is thought that fragile X syndrome affects about 1 in 4,000 males and 1 in 8,000 females in the USA; that is, it affects about twice as many males as it does females. However, about four times as many females appear to be carriers of the altered gene as do males (1:250 females and 1:1000 males).

Standard Therapies

Diagnosis

Over 99% of individuals with fragile X syndrome have a full mutation (over 200 CGG repeats) in the FMR1 gene and abnormal methylation of the FMR1 gene. Molecular genetic testing to determine the number of CGG repeats in the FMR1 gene and testing to determine methylation status of the FMR1 gene are available.



Chromosome analysis using special techniques to induce fragile sites in chromosomes was once used to diagnose fragile X syndrome. Fragile X syndrome is the name given to this condition because some affected individuals have a X chromosome that looked as if it had "snapped" and was held together by the slightest of ties. This technique is no longer used in the diagnosis of this syndrome because it is both less accurate and more costly than are molecular techniques.



Treatment

Treatment of fragile X syndrome includes special education, speech, occupational, and sensory integration training, and behavior modification programs. Other treatment is symptomatic and supportive. Genetic counseling is recommended for affected individuals and their families.

Investigational Therapies

A clinical trial has been approved in Toronto, Canada for the use of minocycline to treat fragile X syndrome. Additional information about this trial is available from the FRAXA Research Foundation or the Fragile X Research Foundation of Canada.



Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

References

TEXTBOOKS

Kasper, DL, Fauci AS, Longo DL, et al. Eds. Harrison's Principles of Internal Medicine.

16th ed. McGraw-Hill Companies. New York, NY; 2005.



Berkow R., ed. The Merck Manual-Home Edition.2nd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2003.



Rimoin D, Connor JM, Pyeritz RP, Korf BR. Eds. Emory and Rimoin's Principles and Practice of Medical Genetics. 4th ed. Churchill Livingstone. New York, NY; 2002:.



Gelehrter TD, Collins FS, Ginsburg D. Principles of Medical Genetics. 2nd ed. Lippincott Williams & Wilkins. Philadelphia, PA; 2002.



Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999.



Hagerman RJ and Hagerman PJ (eds) Fragile X Syndrome: Diagnosis, Treatment, and Research, 3 ed. The Johns Hopkins University Press, Baltimore; 287-338.



JOURNAL ARTICLES

Van Esch H. The fragile X premutation: new insights and clinical consequences. Eur J Med Genet. 2006;49:1-8.



Glover TW, Arlt MF, Casper AM, Durkin SG. Mechanisms of common fragile site instability. Hum Mol Genet. 2005;14 Spec No. 2:R197-205.



Di Prospero NS, Fischbeck KH. Therapeutics development for triplet repeat expansion diseases. Nat Rev Genet. 2005;6:756-65.



Gatchel JR, Zoghbi HY. Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet. 2005;6:743-55.



Willemsen R, Mientjes E, Oostra BA. FXTAS: a progressive neurological syndrome associated with fragile X premutation. Curr Neurol Neurosci Rep. 2005;5:405-10.



Vanderklish PW, Edelman GM. Differential translation and fragile X syndrome. Genes Brain Behav. 2005;4:360-84.



Terracciano A, Chiurazzi P. Neri G. Fragile X syndrome. Am J Med Genet C Semin Med Genet. 2005;137:32-37.



Visootsak J, Warren ST, Anido A, Graham JM Jr. Fragile X syndrome: an update and review for the primary care physician. Clin Pediatr (Phila). 2005;44:371-81.



Wattendorf DJ, Muenke M. Diagnosis and management of fragile X syndrome. Am Fam Physician. 2005;72:111-13.



FROM THE INTERNET

Bilousova T, Dansie L Ngo M, et al. Minocycline Promotes Dendritic Spine Maturation and Improves Behavioral Performance in the Fragile X Mouse Model J. Med. Genet., Oct 2008; doi:10.1136/jmg.2008.061796



Saul RA, Tarleton JC (updated December 2007) FMR1-Related Disorders in: GeneReviews at GeneTests: Medical Genetics Information Resource [database online]. Copyright, University of Washington, Seattle. 1997-2007. Available at http://www.genetests.org.



Fragile X Syndrome. March of Dimes. ©2006. 6pp.

www.marchofdimes.com/professionals/681_9266.asp



Fragile X syndrome. Genetics Home Reference. Last Comprehensive Review: April 2006. 4pp.

http://ghr.nih.gov/condition=fragilexsyndrome



McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Fragile Site Mental Retardation 1 Gene; FMR1. Entry Number;309550: Last Edit Date;4/24/2006.



Jewell J. Fragile X Syndrome. emedicine. Last Updated: November 3, 2005. 8pp.

www.emedicine.com/PED/topic800.htm



The National Fragile X Foundation maintains a comprehensive website of information about fragile X syndrome. Included, among many others are reliable, accessible articles on: What is Fragile X, Genetic Testing for Fragile X, Fragile X syndrome Checklist, Medical Follow-up, etc, etc, etc. Begin with:

www.fragilex.org



Fragile X Syndrome Fact Sheet. The Centre for Genetics Education. nd. 5pp.

www.genetics.com.au/factsheet/32.htm



Fragile X Syndrome (Document ID: 77) Madisons Foundation. nd. 3pp.

www.madisonsfoundation.org/content/3/1/display.asp?did=77



Overview: What is Fragile X syndrome?

Genetic Aspects of Fragile X Syndrome.

Major issue facing Parents and Professionals.

Carolina Fragile X Project. nd. 8pp.

www.fpg.unc.edu/~fx/Pages/overvu.htm



Fragile X Research at FPG. Carolina Fragile X Project. nd. 4pp.

www.fpg.unc.edu/~fx/Pages/resrch.htm

Resources

The Arc

1825 K Street NW, Suite 1200

Washington, DC 20006

Tel: (202)534-3700

Fax: (202)534-3731

Tel: (800)433-5255

TDD: (817)277-0553

Email: info@thearc.org

Internet: http://www.thearc.org



FRAXA Research Foundation

10 Prince Place

Newburyport, MA 01950

USA

Tel: (978)462-1866

Fax: (978)463-9985

Email: info@fraxa.org

Internet: http://www.fraxa.org



National Fragile X Foundation

1615 Bonanza St

Suite 202

Walnut Creek, CA 94596

USA

Tel: (925)938-9300

Fax: (925)938-9315

Tel: (800)688-8765

Email: natlfx@FragileX.org

Internet: http://www.fragilex.org



New York State Office for People with Developmental Disabilities

44 Holland Avenue

Albany, NY 12229

Tel: (866)946-9733

TDD: (866)933-4889

Email: Commissioners.Correspondence.Unit@omr.state.ny.us

Internet: http://www.omr.state.ny.us/ws/ws_ibr_resources.jsp



NIH/National Institute on Aging

31 Center Drive, MSC 2292

Building 31

Room 5C27

Bethesda, MD 20892

Tel: (301)496-1752

Fax: (301)496-1072

Tel: (800)222-2225

TDD: (800)222-4225

Email: bapquery@nia.nih.gov

Internet: http://www.nih.gov/nia



NIH/National Institute of Child Health and Human Development

31 Center Dr

Building 31, Room 2A32

MSC2425

Bethesda, MD 20892

Fax: (866)760-5947

Tel: (800)370-2943

TDD: (888)320-6942

Email: NICHDInformationResourceCenter@mail.nih.gov

Internet: http://www.nichd.nih.gov/



New Horizons Un-Limited, Inc.

811 East Wisconsin Ave

P.O. Box 510034

Milwaukee, WI 53203

USA

Tel: (414)299-0124

Fax: (414)347-1977

Email: horizons@new-horizons.org

Internet: http://www.new-horizons.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



Let Them Hear Foundation

1900 University Avenue, Suite 101

East Palo Alto, CA 94303

Tel: (650)462-3174

Fax: (650)462-3144

Email: info@letthemhear.org

Internet: http://www.letthemhear.org



Fragile X Society

Road End House

6 Stortford Road

Great Dunmow

Essex, CM6 1DA

United Kingdom

Tel: 004401371875100

Email: info@fragilex.org.uk

Internet: http://www.fragilex.org.uk



Medical Home Portal

Dept. of Pediatrics

University of Utah

P.O. Box 581289

Salt Lake City, UT 84158

Tel: (801)587-9978

Fax: (801)581-3899

Email: mindy.tueller@utah.edu

Internet: http://www.medicalhomeportal.org



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.

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