What is Fragile X

Facts

The short answer is that Fragile X syndrome (also called Fragile X) is the most common inherited form of mental impairment. It is caused when a mutation in a gene prevents the body from making an important protein. This impairment can range from learning disabilities to more severe cognitive or intellectual disabilities. FXS is the most common known cause of autism or "autistic-like" behaviors. Symptoms also can include characteristic physical and behavioral features and delays in speech and language development. The syndrome affects approximately one in 3,600 males and one in 8,000 females. It results from a change, or mutation, in a single gene, which can be passed from one generation to the next. Fragile X appears in families of every ethnic group and income level.

The long answer of what Fragile X is...

Genes provide blueprints for the body, giving instructions on how to build each part of a cell. In people with Fragile X, sections of a blueprint become repeated to the point that the instructions don't make sense anymore. The mutation is in the DNA of the X chromosome. The gene appears in three forms that are defined by the number of repeats of a pattern of DNA called CGG repeats

less than 60 CGG repeats have a normal gene
60-200 CGG repeats have a pre-mutation, which means they carry an unstable mutation which can expand in future generations. Some females with a pre-mutation will experience early menopause. (POI) Additionally, some older adults with pre-mutations may develop a neurological condition called FXTAS (often misdiagnosed as a "Parkinson's-like" condition). Approximately 1 in 250 females and 1 in 800 males carry the pre-mutation.
Greater than 200 repeats have a full mutation which causes fragile X syndrome. When that happens, the cell can no longer decipher the instructions from the brain. With no instructions to follow, the final product, a protein called FMRP, cannot be made.

One function of the FMRP protein in the brain is to put the brakes on another protein in the brain, called MGluR5. MGluR5 tells the neurons (brain cells) to grow dendrites, which are long, narrow parts that allow them to attach to other neurons. When the dendrites are the right size and shape, FMRP makes MGluR5 tell the neurons to stop. When FMRP is missing, the dendrites grow wild and uncontrolled. The brain uses the dendrites to send signals from one cell to another. When the dendrite is the right shape and size, it’s easy for the signal to get from one cell to another, like a car getting from Exit 1 to Exit 2 on the highway. But when the dendrites are out of control, it’s as if the highway between the two exits has sprouted many other exits and detours, and it’s a lot easier to get lost. This is what happens in your child’s brain—signals get lost on their way from one cell to another. This makes it hard to learn, and hard to respond to stimuli in the same way as people whose neurons can communicate easily.

While fathers cannot pass the syndrome on to their sons (only daughters), mothers who are carriers may pass severe forms of Fragile X to both male and female children. This is because the syndrome is caused by a mutation in a specific gene on the X chromosome known as FMR1.

Learn the signs and symptoms

For individuals with Fragile X Syndrome, effects can vary from subtle developmental delays to major impairments. Males with the full mutation are more severely affected than females.

Most males will have mild to severe mental impairment with cognitive and communication skills most likely to be affected. For boys, who are more severely affected, speech and language disorders are very significant. Delayed speech and language development is often the first sign to parents that their sons have developmental delays. Oral-motor weaknesses, receptive-expressive language gaps, and repetitive speech characterize their language. Most males with Fragile X may stutter or leave sounds out of their words. Many repeat themselves, restart the same sentence many times, or ask the same question again and again. Some may talk too fast, mumble, or speak in a loud, high voice. Significant cognitive, sensory, and behavioral issues impact these speech and language characteristics. Also, around 33% of males with Fragile X meet all the criteria for autism; the remaining may show some signs of autism, but tend to be mostly social.

Males have several distinguishing physical features, including large ears, loose joints and muscles, and an elongated face. Early recurrent middle ear infections are also very common. Once males reach puberty many boys develop macro-orchidism. It is a condition where the testicles may grow up to twice their normal size. This condition is not due to hormonal imbalance and does not affect sexual development.

Many individuals with Fragile X are overwhelmed with sensory input. They simply have a difficult time processing the information. Children with Fragile X may seem shy, anxious, and inattentive. Hyper arousal, a tendency to become easily over stimulated and to overreact to changes in environment or routines is a common condition. They may be easily distracted by slight sounds in the room. They may be bothered by the texture of their clothes against their skin, too. Some children try to avoid being touched, and others might crave it.

About 20 percent of children with Fragile X also experience seizures. In most cases, seizures are successfully treated with medication and disappear by adolescence.

Females with the full mutation may have milder symptoms. About one third will exhibit normal development, another third will exhibit learning disabilities, and about one third will have mild to moderate mental impairment. Females the full mutation will also be shy and exhibit social problems.

It is estimated that 1 in 129 females in the general population carry the fragile x pre-mutation. Of that, about 20% will be diagnosed with premature ovarian impairment (POI). It is a problem with ovarian function that can lead to infertility and early menopause prior to age 40. Some women even experience POI as early as their mid-twenties. It is important for women to know whether or not they have the pre-mutation gene, and to have this knowledge early enough, so that they can consider their options for having a family.

Fragile X associated tremor/ataxia syndrome (FXTAS) is a condition that causes balance, tremor and memory problems in some older male carriers of the fragile X pre-mutation. It has been seen, but much less common in female carriers.

Diagnosis

Screening for Fragile X involves a simple blood test, which can accurately diagnose the syndrome 99 percent of the time. This DNA test, available since the gene was first identified in 1991 can detect Fragile X in normal carriers and in those affected, but it cannot tell from that analysis if the child is or will be intellectually impaired or the severity of many of the symptoms. Unfortunately, diagnosis of fragile X syndrome is often delayed, preventing the possibility of early intervention services and family planning.

There is currently no cure as such for Fragile X, but once it has been diagnosed there are a number of management strategies that can help many children and adults.

Resources

South Florida Fragile X Clinic
1051 NW 10th Ave, BRB-336 (M-860)
Miami, FL 33136
Kimberly Glaser, M.S., GC
Tel: (305) 243-9461
E-mail: kglaser@med.miami.edu
http://medgen.med.miami.edu/fragile-x-clinic-sffxc

UC Davis MIND Institute
2825 50th Street
Sacramento, California 95817
Contact Information:
Julaila Musgrove, New Patient Referral Coordinator
916-703-0308
www.ucdmc.ucdavis.edu/mindinstitute/clinic/index.html

National Fragile X Foundation
2100 M St., NW
Ste.170 Box 302
Washington, DC 20037-1233
Phone: 800-688-8765
Fax: 202-747-6208
Email: natlfx@fragilex.org
Website: www.fragilex.org

American Academy of Pediatrics
Available online at: www.aap.org