Fragile XE syndrome

Title

Other Names:

FRAXE syndrome; Fragile site, folic acid type; X-linked mental retardation associated with fragile site FRAXE

Categories:

Congenital and Genetic Diseases; Nervous System Diseases

Summary Summary

Fragile XE syndrome (FRAXE) is a genetic condition associated with mild to borderline intellectual disabilities with physical features differing from person to person. The characteristic features are learning difficulties, often a consequence of communication problems (speech delay, poor writing skills), hyperactivity, and a shortened attention span. Nearly all cases of FRAXE are caused by a specific type of mutation, called a trinucleotide repeat expansion, in the AFF2 gene, which is located on the X chromosome. A trinucleotide repeat expansion occurs when there is an abnormally large number of repeats of a specific sequence of three nucleotides (building block of DNA) within our DNA. The repeating nucleotides in FRAXE syndrome are CCG. When the number of CCG repeats is over 200, people typically have the signs and symptoms seen in FRAXE. FRAXE is inherited in an X-linked manner.^[1]^[2]^[3] Although there is no specific treatment for FRAXE, there may be ways to manage the symptoms. A team of doctors or specialists is often needed to figure out the treatment options for each person.

Last updated: 9/9/2016

Symptoms Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

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Medical Terms	Other Names	Learn More: HPO ID
30%-79% of people have these symptoms
Aggressive behavior	Aggression Aggressive behaviour Aggressiveness [ more ]	0000718
Agitation		0000713
Autistic behavior		0000729
Clumsiness		0002312
Delayed speech and language development	Deficiency of speech development Delayed language development Delayed speech Delayed speech acquisition Delayed speech development Impaired speech and language development Impaired speech development Language delay Language delayed Language development deficit Late-onset speech development Poor language development Speech and language delay Speech and language difficulties Speech delay [ more ]	0000750
Epicanthus	Eye folds Prominent eye folds [ more ]	0000286
Hoarse voice	Hoarseness Husky voice [ more ]	0001609
Hyperactivity	More active than typical	0000752
Impulsivity	Impulsive	0100710
Intellectual disability	Mental deficiency Mental retardation Mental retardation, nonspecific Mental-retardation [ more ]	0001249
Intrauterine growth retardation	Prenatal growth deficiency Prenatal growth retardation [ more ]	0001511
Obsessive-compulsive behavior	Obsessive compulsive behavior	0000722
Prominent ear helix		0009904
Prominent nasal bridge	Elevated nasal bridge High nasal bridge Prominent bridge of nose Prominent nasal root Protruding bridge of nose Protruding nasal bridge [ more ]	0000426
Recurrent hand flapping		0100023
Short stature	Decreased body height Small stature [ more ]	0004322
Specific learning disability		0001328
Thick vermilion border	Full lips Increased volume of lip Plump lips Prominent lips Thick lips [ more ]	0012471
5%-29% of people have these symptoms
Clinodactyly of the 5th finger	Permanent curving of the pinkie finger	0004209
Macrocephaly	Increased size of skull Large head Large head circumference [ more ]	0000256
Stereotypical body rocking		0012172
Percent of people who have these symptoms is not available through HPO
Abnormality of metabolism/homeostasis	Laboratory abnormality Metabolism abnormality [ more ]	0001939
X-linked inheritance		0001417
X-linked recessive inheritance		0001419

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Do you have more information about symptoms of this disease? We want to hear from you.

Last updated: 9/1/2020

Do you have updated information on this disease? We want to hear from you.

Cause Cause

FRAXE is a genetic disorder caused by mutations in the AFF2 gene. This gene provides instructions for making a protein whose function is not well understood. Nearly all cases of FRAXE are caused by a specific type of mutation, called a trinucleotide repeat. A trinucleotide repeat is an abnormal expansion of three repeats of our DNA building blocks (nucleotides). The repeating nucleotides in FRAXE are CCG. Normally, the involved segment of three nucleotides is repeated approximately 4 to 40 times. However, in people with FRAXE, the CCG segment is repeated more than 200 times, which makes this region of the gene unstable or fragile. As a result, the AFF2 gene is turned off (silenced), and no AFF2 protein is produced. It is unclear how a shortage of this protein leads to intellectual disability in people with FRAXE. Some people with FRAXE have a deletion of genetic material in the AFF2 gene.^[4]^[2]^[3]

People with 50 to 200 CCG repeats are said to have an AFF2 gene premutation. Current research suggests that people with a premutation do not have associated cognitive problems.^[2]

Last updated: 9/9/2016

Diagnosis Diagnosis

The diagnosis of FRAXE is made based on signs and symptoms and genetic testing to confirm either a trinucleotide repeat expansion or a deletion within the AFF2 gene.^[3]

Last updated: 9/9/2016

Testing Resources

The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

Find a Specialist Find a Specialist

If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from Genetics Home Reference.

Research Research

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

The National Fragile X Foundation provides a state by state list of clinical trials involving fragile X-associated disorders. Click on National Fragile X Foundation to view the list.

Organizations Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

Developmental Delay Resources (DDR)
5801 Beacon Street
Pittsburgh, PA 15217
Toll-free: 800-497-0944
Fax: 412-422-1374
E-mail: devdelay@mindspring.com
Website: http://www.devdelay.org

Organizations Providing General Support

American Association on Intellectual and Developmental Disabilities
501 3rd Street NW
Suite 200
Washington, DC 20001
Toll-free: (800) 424-3688
Telephone: (202) 387-1968
Fax: (202) 387-2193
Website: http://www.aaidd.org
The Society for Developmental and Behavioral Pediatrics
6728 Old McLean Village Drive
McLean, VA 22101
Telephone: 703-556-9222
E-mail: info@sdbp.org
Website: http://www.sdbp.org/index.cfm

Do you know of an organization? We want to hear from you.

Learn More Learn More

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

The National Center on Birth Defects and Developmental Disabilities (NCBDDD) at the Center for Disease Control and Prevention (CDC) provides information about developmental disabilities, including intellectual disability. To view this information, click on the link below.
Link: http://www.cdc.gov/ncbddd/dd/ddmr.htm
Genetics Home Reference (GHR) contains information on Fragile XE syndrome. This website is maintained by the National Library of Medicine.

In-Depth Information

The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine.
Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
PubMed is a searchable database of medical literature and lists journal articles that discuss Fragile XE syndrome. Click on the link to view a sample search on this topic.

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References References

Gecz J. The FMR2 gene, FRAXE and non-specific X-linked mental retardation: clinical and molecular aspects. Ann. Hum. Genet. Mar 2000; 64(Pt 2):95-106. http://www.ncbi.nlm.nih.gov/pubmed/?term=11246464.
fragile XE syndrome. Genetics Home Reference. January 2014; https://ghr.nlm.nih.gov/condition/fragile-xe-syndrome.
Victor A. McKusick. MENTAL RETARDATION, X-LINKED, ASSOCIATED WITH FRAGILE SITE FRAXE. In: Cassandra L. Kniffin. OMIM. 9/22/2011; http://omim.org/entry/309548.
Rimoin DL, Connor JM, Pyeritz RE, Korf BR. Emery and Rimoin's Principles and Practice of Medical Genetics, 5th ed. Philadelphia: Churchill Livingstone Elsevier; 2007;