Fragile X Syndrome

What Is Fragile X Syndrome? 

Fragile X syndrome is a genetic condition involving changes in a person’s X chromosome that triggers several developmental challenges such as cognitive impairment and learning disabilities.

Specifically, this condition can result in attention deficit disorder, features of autism spectrum disorders that affect social interaction and communication, anxiety, hyperactivity, seizures, and other related symptoms. 

Several physical features worsen with age in most males and about half of all females. That is consistent with the fact that overall, males are more severely affected by Fragile X that females.

These features can include a long and narrow face, large ears, flat feet, a prominent jaw and forehead, unusually flexible fingers, and enlarged testicles in males ¹.

Fragile X syndrome is present in about 1 in 4,000 males and 1 in 8,000 females. It's the most common form of inherited intellectual disability in males. 

It is also known by several other names, including:

• fra(X) syndrome
• FRAXA syndrome
• FXS
• marker X syndrome
• Martin-Bell syndrome
• X-linked mental retardation and macroorchidism

The Three Fragile X-Associated Disorders

There are three Fragile X-associated disorders (FXD) that are a family of genetic conditions impacting people in several possible ways. These disorders are a group of conditions called trinucleotide repeat disorders.

Specifically, they are:

• Fragile X Syndrome (FXS)
• Fragile X-associated tremor/ataxia syndrome (FXTAS) 
• Fragile X-associated primary ovarian insufficiency (FXPOI)

Changes in the FMR1 gene cause all of these conditions. FXS is caused by a full mutation of the FMR1 gene. The premutation of the FMR1 gene causes FXTAS and FXPOI.

To better understand each of these Fragile X-associated disorders, you need to first understand some basic genetic science and the difference between full mutation and premutation.

The Differences Between Full Mutation and Premutation

Every person has 46 chromosomes in our cells. Forty-four of these are numbered 1 through 22 in pairs. Females have two X chromosomes, and males have one X and one Y chromosome.

There are a lot of genes on each chromosome. Based on where it lies on the chromosome, each gene is given an address, much like the post office assigns addresses to homes and businesses on streets. For the record, the address of the FMR1 gene is Xq27.3.

Everyone has the FMR1 gene. This gene manufactures a protein called FMRP. This protein is found in all cells but is especially prevalent in dendrites, which are the part of nerve cells that communicate with other nerve cells.

When the FMR1 gene mutates, this can impact the amount of protein produced in the cell. It can result in a decrease or a complete failure to produce any protein at all.

With a full mutation, the FMR1 gene is shut down, resulting in little or no production of FMRP. An individual can also have a premutation as well.

Most people with a premutation are intellectually normal. Sometimes, people with a premutation have lower levels of the gene's protein resulting in some mild symptoms of FXS.

What determines these differences?

The FMR1 gene can appear in a cell in four forms. The four forms are defined by the number of repeats of a pattern of DNA.

These are called CGG repeats. A CGG repeat in the FMR1 gene can occur anywhere from 30 to 1,000 times.

Medical professionals measure the number of repeats when testing for Fragile X syndrome. The number of repeats determines if a gene is normal, has a premutation, or a full mutation.

A diagnosis is made based on the following number of CGG repeats:

Normal: Individuals with less than 45 CGG repeats have a normal FMR1 gene.

Intermediate: People with 45-54 CGG repeats have an "intermediate" or "gray zone allele." This range does not cause any of the known Fragile X associated disorders.

Premutation: People with 55-200 CGG repeats have a premutation. That means they carry an unstable mutation of the gene that can expand in future generations.

If that happens, it can cause Fragile X syndrome in their children or grandchildren. Individuals with a premutation can also develop FXTAS or FXPOI themselves.

Full Mutation: People with more than 200 CGG repeats have a full mutation of the FMR1 gene, which causes Fragile X syndrome. Most full mutations have some degree of methylation, which is the process that "turns off" the gene.

When the stretch of DNA expands beyond a certain length, the FMR1 gene is switched off. As a result, it does not produce the protein that it is usually made.

Fragile X Syndrome (FXS)

FXS is caused by a full mutation of the FMR1 gene.

The estimated prevalence of FXS in males is approximately 1 in 3,600 to 4,000, and in females is about 1 in 4,000 to 6,000 ².

The reason FXS is lower in females because all males with an FMR1 full mutation will have Fragile X syndrome, but some females with an FMR1 full mutation will not have behavioral, cognitive, or physical features of FXS.

FXS is characterized in males with behavioral issues such as ADD, ADHD, autism and autistic behaviors, social anxiety, sensory disorders, and a heightened risk of aggression. Females may also have these behavioral characteristics, but they are often less severe.

FXS also produces moderate to severe intellectual disabilities. Most males exhibit several intellectual disabilities.

Only about one in three females have a significant intellectual disability but may suffer from emotional or mental health issues, and general or social anxiety.

Physical features of FXS can include a long face, soft skin, large ear, and enlarged testicles in post-puberty males. Other physical issues may consist of ear infections, flat feet, and hyper-flexible joints and fingers.

A small percentage of females with FXS won’t have any apparent behavioral, intellectual, or physical signs of the condition. Many times, they are only tested and diagnosed after another family member has been diagnosed.

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)

FXTAS is a neurodegenerative disorder that usually affects males over 50 years old ³. Only a small percentage of females are affected by FXTAS, and their symptoms are generally milder.

FXTAS is a relatively newly diagnosed disorder. Dr. Randi Hagerman first described it at UC Davis in 2001.

Dr. Hagerman noticed a pattern of grandfathers of children with Fragile X syndrome who were being diagnosed with Parkinson's disease, Alzheimer's disease, various balance problems (ataxias), tremors, and other neurological conditions.

Through family medical histories and MRI exams, the team at UC Davis was able to link MRI changes in their brains and a diagnosis of FMR1 premutations (CGG repeats between 55-200). Based on these findings, FXTAS was identified in 2003.

Research suggests that about 30-40% of male FMR1 gene premutation carriers over 50 years old will eventually exhibit some features of FXTAS in the future. For females, this number ranges between 8-16% of carriers ⁴.

The chance of developing defining symptoms of FXTAS increases with age.

• Ages 50-59 the chance is about 17%.
• Ages 60-69, about 38%.
• Ages 70-79, about 47%.
• Over 80 years old, about 75% will develop symptoms of FXTAS ⁵.

The symptoms of FXTAS are divided into major and minor clinical and MRI findings. A diagnosis is then categorized into definite, probable, or possible FXTAS.

Major FXTAS symptoms include intention tremor (hand tremors when using utensils), gait ataxias (balance problems or general instability when going up or down stairs, curbs, etc.), MRI findings, and neuropathology findings.

Minor FXTAS symptoms include Parkinsonism (resting tremors), short-term memory issues (rapid and dramatic), and problems with making decisions (including the ability to adapt to change or complete activities).

Other symptoms that are not considered part of an official diagnosis, but may still exist, include mood instability, neuropathy, impotence, loss of bladder or bowel functions, cognitive declines, high blood pressure, fibromyalgia, and thyroid problems ⁶.

Fragile X-Associated Primary Ovarian Insufficiency (FXPOI)

FXPOI is caused by a premutation of the FMR1 gene and refers to a range of disorders related to reduced ovarian function. That includes infertility and early menopause in women under 40 years old.

Ovaries in women with FXPOI may act and resemble the ovaries of an older woman. That includes a decline in the number and the quality of available eggs in the reproductive cycle.

FXPOI is present in about 20-25% of adult female FMR1 premutation carriers. Overall, about 2% of women with reproductive ovarian insufficiencies are diagnosed with the FMR1 premutation.

FXPOI is characterized by absent or irregular menstrual cycles, hot flashes, low fertility or infertility, premature ovarian failure (the complete cessation of menstrual periods before a woman turns 40).

Some women with FXPOI can still get pregnant in some cases because ovaries may still release viable eggs from time to time.

What Causes Fragile X Syndrome?

Fragile X syndrome and Fragile X-associated conditions are caused by a mutation or premutation of the FMR1 gene.

Mutations in the FMR1 gene often causes decreased or complete absence of FMRP (sometimes referred to as the fragile X mental retardation 1 protein), an essential protein needed for healthy development in each cell.

When the gene is turned off, the individual does not make this protein in a process known as methylation. Methylation is what turns off the FMR1 gene.

The genes can change sizes from generation to generation and become more unstable. When this happens, signs and symptoms of Fragile X syndrome can become more pronounced.

Often, a gene will begin as a premutation and eventually expand to a full mutation in later generations.

The Genetic Inheritance Pattern of Fragile X Syndrome

Fragile X syndrome is an “X-linked” condition. That means the gene is on the X chromosome. Because of this, how the mutated gene is passed on from generation to generation differs between mothers and fathers.

Because a woman has two X chromosomes, a mother with a permutated or fully mutated FMR1 gene has a 50% chance of passing the mutation along in each pregnancy.

The mother also has a 50% chance of passing on her normal X chromosome as well. In most cases, only one of her X chromosomes has the FMR1 mutation.

If she has a premutation, it can be passed to a child as a premutation or as a full mutation. If she has a full mutation, then it will always pass along as a full mutation.

The chance of the premutation expanding to a full mutation depends on the size of the mother’s premutation. Mothers with a larger CGG repeat number have a higher chance that a premutation will expand to a full mutation if it is passed on to a child. 

Men have only one x chromosome, so fathers who carry the premutation will pass it along to all of their daughters and none of their sons. That is because they only pass along their Y chromosome to their sons.

According to researchers, there have been no reports of a premutation passed from a father to his daughter and then expanding to a full mutation. That appears only to occur when passed from a mother to her children.

Signs & Symptoms of Fragile X Syndrome

Physical Signs

Several possible physical signs characterize fragile X syndrome. These can be hard to recognize in babies and toddlers. Often signs will become more obvious with age, including: 

• long face
• large forehead
• soft skin
• large prominent ears
• flat feet
• hyperextensible joints, especially fingers
• low muscle tone
• males may have large testes after puberty (macroorchidism)

Not every person with Fragile X will have all of these signs.

Symptoms

• mild to severe intellectual disabilities
• attention deficit disorder and hyperactivity, especially in young children
• anxiety 
• unstable moods
• problems with tremors and reduced coordination
• delays in crawling, walking or twisting
• hand biting
• autism spectrum disorders, such as hand-flapping or not making eye contact, and issues that affect communication and social interaction. About 30% of boys with Fragile X meet the full criteria for autism ⁷. Others tend to be very social and interested in other people.

• sensory integration problems, including hypersensitivity to loud noises or bright lights

• speech delay, with expressive language more severely affected than receptive language ⁸. Despite delays in learning how to talk, most individuals with Fragile X do learn to speak.
• seizures (epilepsy) affects about 25% of people with Fragile X ⁹

• In most instances, girls are affected less by Fragile X than boys. However, there is a lot of variation and no reliable way to predict impacts.

• Research has shown that while most boys have some form of intellectual impairment, only one-third to one-half of girls have major intellectual challenges. All others either have normal IQs or learning disabilities.
• Math is challenging for many girls. 
• Women can have premature menopause or difficulty becoming pregnant. 

Possible Complications Associated with Fragile X Syndrome

Compared to many other genetic conditions, Fragile X syndrome does not cause a lot of medical complications, though there are a few.

The severity of the complications will vary, depending on the type and severity of a person’s symptoms.

For children, these possible complications can include:

• ear infections
• eye problems, including strabismus (inability to focus both eyes on an object), hyperopia (far-sightedness) and astigmatism
• seizures
• toilet training problems

Adults may develop the following complications:

• mitral valve prolapse (leaky heart valve)
• aortic enlargement in a small proportion
• high blood pressure, treated with medication
• scoliosis

Diagnosis and Testing for Fragile X Syndrome

DNA testing for Fragile X syndrome is accurate and straightforward. It can detect affected individuals and carriers who show no outward symptoms.

Testing should be considered for anyone who shows signs of developmental delay or autism, especially with the signs are subtle, as they may be in younger children.

Testing is done by drawing a blood sample and then sent to a lab for analysis. Results can take several weeks.

Fragile X prenatal testing is also available to determine if an unborn child is affected. It can be done either by amniocentesis or by chorionic villus sampling (CVS).

You may need to request this specific test since it is not typically included in routine prenatal screenings. Talk to your doctor or a genetic counselor if you have questions or think a prenatal test might be a good idea.

The American Society for Reproductive Medicine and American College of Obstetrics and Gynecology recommends FMR1 testing for all women with ovarian insufficiency or elevated FSH levels. FSH is a hormone that reflects a woman’s level of ovarian function.

FSH levels increase as women approach menopause or if ovaries are not functioning properly for a woman’s age.

Testing may also make sense if a family member has already been diagnosed with any form of FMR1 related disorder.

Treatment and Care Options for Fragile X Syndrome

Because every person may have different signs and symptoms of Fragile X syndrome, there is no uniform treatment for the condition.

People who receive medications, therapies, and educational services have the best chance of enjoying their fullest skills and capabilities.

Early intervention is the key. Because symptoms can appear at a young age when a child’s brain is still forming, giving the child the best chance at a full life starts as soon as possible.

The sooner that a child with Fragile X syndrome gets the help they need, the better the opportunity there is for them to respond.

Parents can assist by recognizing and accepting the need for special education, avoiding excessive stimulation, and tailoring special education to counter specific learning disabilities. Medications can also play a key role in lessening behavioral issues that impact social interactions.

The American Academy of Pediatrics Guidelines has issued guidelines that can give direction. Read Health Supervision for Children with Fragile X for more treatment guidelines.

Also, when seeking medical treatment, look for professionals who have specific experience with Fragile X syndrome. You can find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. 

Also, consider contacting a university or tertiary medical center in your area. These facilities tend to see more complex cases and have the latest technology and treatments.

To find a professional who specializes in genetics, ask your doctor for a referral. You can also search for one yourself. Online directories are available through the American College of Medical Genetics and the National Society of Genetic Counselors.

Fragile X Guide for Parents by Parents published by the FRAXA Research Foundation is also a great place to get communal support for treatment and information.

Although there are no medicines that are specifically approved to treat Fragile X, many medications can help treat certain symptoms. Check out A Medication Guide for Fragile X Syndrome by Dr. Michael Tranfaglia for more details on medication options.

The Prognosis of Fragile X Syndrome

The prognosis for people living with Fragile X syndrome is normal in most cases. While some people are prone to more medical issues, many affected people lead active lifestyles and have overall good health.

The key to an optimum long-term prognosis is engaging in regular preventative medical checkups and being aware of the increased health risks if you are an affected individual.

What to do Next: Living with Fragile X Syndrome

If you or a family member are newly diagnosed with Fragile X syndrome, you will probably have a lot of questions. Fortunately, there is a large amount of information and research available on the subject.

Talk to your doctor or a genetic counselor to help guide you to the resources you need to become more comfortable in your level of understanding.

Some of the medical information associated with Fragile X is complicated, so give yourself ample time to digest it, and don't be afraid to ask as many questions as you need to until you are satisfied with your base of knowledge.

You will probably want to notify family members, friends, your child's school, and others who interact with your child. Part of this will be to help you access services, and part of it will be to assist you in communal management of the affected person's condition.

The National Fragile X Foundation publishes one excellent resource. You can download the Fragile X-Associated Disorders Handbook (3rd Edition): A Handbook for Families, Health Care Providers, Counselors, and Educators. It covers a wide variety of situations and message points to assist you.

When you do notify friends and family members, understand that there will be a wide range of reactions from support, to denial, disbelief or indifference. Some of these feelings take time to work through before a higher degree of support kicks in.

Guilt may also be present if a family member learns they are a carrier for the genetic mutation. They may be distraught at the possibility of being the person linked to passing Fragile X on to other family members.

As you educate yourself more on Fragile X, you can be an ongoing resource for people in your life. Make yourself available to those who have questions. Keep the lines of communication open.

For More Information on Fragile X Syndrome

There are several resources you can tap into for more information about Fragile X syndrome. Many of the entities listed below have significant information resources for patients and often serve as catalysts for better treatments and possible Fragile X syndrome cures.

These organizations can also be excellent sources for accessing experts, medical advisors, doctors, and clinics.

Developmental Delay Resources (DDR)
5801 Beacon Street
Pittsburgh, PA 15217
Toll-free: 800-497-0944
E-mail: [email protected]
Website: http://www.devdelay.org 

FRAXA Research Foundation
10 Prince Place
Newburyport, MA 01950
Telephone: (978) 462-1866
E-mail: [email protected]
Website: http://www.fraxa.org 

National Fragile X Foundation
2100 M St., NW
Ste.170 Box 302
Washington, DC 20037-1233
Toll-free: 800-688-8765
E-mail: [email protected]
Website: http://www.FragileX.org 

The Fragile X Society
Road End House
6 Stortford Road
Great Dunmow, Essex, CM6 1DA
United Kingdom
Telephone: 00 44 (0)1371 875100
Fax: 00 44 (0)1371 859915
E-mail: [email protected]
Website: http://www.fragilex.org.uk 

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: [email protected]
Website: http://www.sdbp.org/index.cfm 

Clinical Research Resources

ClinicalTrials.gov lists trials related to Fragile X syndrome.

The National Fragile X Foundation has a state by state list of clinical trials involving fragile X-associated disorders.

The FRAXA Research Foundation lists clinical trials looking for participants. You can view the list to find study opportunities near you.

Fragile X Research Registry

Resources from the National Fragile X Foundation 

The National Fragile X Foundation has published many Consensus Documents:

Behavioral Challenges in Fragile X Syndrome UPDATED

Educational Guidelines for Fragile X Syndrome: General UPDATED

Educational Guidelines for Fragile X Syndrome: Early Childhood (Birth to 5 Years) UPDATED

Educational Guidelines for Fragile X Syndrome: Elementary Students  UPDATED

Educational Guidelines for Fragile X Syndrome: Middle and High School Students UPDATED

Fragile X-Associated Primary Ovarian Insufficiency (FXPOI)UPDATED

Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) UPDATED

Genetic Counseling & Family Support UPDATED

Powered by Froala Editor