Information on the following diseases can be found in the Related Disorders section of this report:

• Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)
• Fragile XE Syndrome (FRAXE)
• FMR1-Related Premature Ovarian Failure (POF)
• Renpenning Syndrome

Fragile X syndrome is characterized by moderate mental retardation in affected males and mild mental retardation 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.

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 the 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.

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).

The FMR1 gene is associated with two other disorders and these conditions have been termed FMR1-related disorders:

Fragile X-associated tremor/ataxia syndrome (FXTAS) is characterized by a progressive adult-onset movement abnormalities (ataxia) and rhythmic, involuntary movements (tremors) that affect mostly men. Individuals with this condition have a premutation in the FMR1 gene (59-200 CGG repeats).

FMR1-related premature ovarian failure is defined as menopause before age 40 years in women who have a premutation in the FMR1 gene (59-200 CGG repeats). The risk of premature ovarian failure (POF) in premutation carriers is approximately 21%. Women with POF of unknown cause have a risk of 1/50 to be a carrier of a premutation in the FMR1 gene.

Some symptoms of the following disorders can be similar to those of fragile X syndrome. Comparisons may be useful for a differential diagnosis:

Fragile XE syndrome, also known as fragile XE mental retardation (FRAXE) is caused by an abnormal FMR2 gene located on the X chromosome very close to the site of the FMR1 gene. The normal FRM2 gene contains 6-35 copies of CGG and people with the disorder have over 200 copies of CGG in the FMR2 gene. The effect of FMR2 genes with 35-200 copies of CGG has not yet been determined. Common symptoms of FRAXE include mild mental retardation, learning deficits, and possible developmental delays.

Renpenning syndrome is one of the chromosome X-linked mental retardation disorders that affects males almost to the exclusion of females. Very, very, very rarely females will present with this syndrome. It is characterized by mental retardation that can be severe, short stature, a smaller than normal head circumference (microcephaly), and small testes. The syndrome has been mapped to gene map locus Xp11.2-p11.4 and the term "Renpenning syndrome" should be limited to the condition that maps to this region. The prevalence is unknown.

Developmental delay is present early with males learning to walk at age 2–3 years and able to say simple words at age 3–4 years. Although an affected male may appear physically normal, his head circumference and height will be at the lower limits of normal. After puberty, testes will be smaller than normal. Diagnosis is very difficult especially if there is only one male with mental retardation in a family. The diagnosis must be based on evidence of inheritance as an X-linked trait, and determining that the affected gene is located on the short arm (at Xp11.1-p11.4) of the X chromosome.

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.

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 website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

At the present time (06/06), there is one clinical trial listed for fragile X syndrome. The trial is sponsored by Stanford University and is designed to determine if donepezil has any beneficial effect on behavior or cognition in subjects with fragile X syndrome. The clinical trial identification number, used in correspondence with NIH, is BCT00220584.

The drug guanfacine (Tenex) has been designated as an orphan product for the treatment of fragile X syndrome. It is not clear that the drug has been approved for marketing. It is manufactured by:

Watson Laboratories, Inc.
311 Bonnie Circle
PO Box 1900
Corona, CA 91718

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.

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

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

Kasper, DL, Fauci AS, Longo DL, et al. Eds. Harrison’s Principles of Internal Medicine.
16th ed. McGraw-Hill Companies. New York, NY; 2005:.

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:.


REVIEW 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
Fragile X syndrome. Genetics Home Reference. Last Comprehensive Review: April 2006. 4pp.
http://ghr.nih.gov/condition=fragilexsyndrome

Saul RA, Tarleton JC. FMR1-Related Disorders. GENEReviews. Last Revision: 25 April 2006. 28pp.
www.genetests.org

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. March of Dimes. ©2006. 6pp.
www.marchofdimes.com/professionals/681_9266.asp

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