What Is Fragile X Syndrome?
Fragile X syndrome is one of three fragile X-associated disorders (FXD) caused by a genetic mutation of the X chromosome. It goes by several other names, including fra(X), FRAXA, or marker X syndrome, as well as X-linked mental retardation and macroorchidism. Its original name was Martin-Bell syndrome, after the men who discovered the mutation in 1943.
The severity of the mutation determines whether a person has fragile X syndrome or one of its two associated disorders, fragile X-associated primary ovarian insufficiency and fragile X-associated tremor/ataxia syndrome. Because females have two X chromosomes and males have only one, the effects of fragile X syndrome vary according to sex, with males tending to have more severe symptoms than females.
1. Physical Characteristics
Males with fragile X syndrome have jaws, foreheads, and ears that protrude from an otherwise thin and elongated face. Their muscles and skin are soft, their feet flat, and their joints able to hyperextend. The roof of the mouth is arched, and many have macroorchidism, or enlarged testicles. Many of these features are not conspicuous until after a boy reaches puberty.
Approximately 40% to 50% of females with fragile X syndrome exhibit at least some of the same physical characteristics as males, typically exhibiting a long face and protruding ears. However, many go undiagnosed or discover they have the mutation only after undergoing a genetic test.
2. Cognitive Impairment
Some males with fragile X have severe intellectual impairment, sometimes with an adult I.Q. of 40. Sequential processing and short-term memory are especially impaired. Others have only slight learning disabilities.
Thirty-five to 50% of females with fragile X have some type of significant intellectual limitation. Others may have milder impairments or be cognitively unaffected. Both boys and girls sometimes have delayed speech development, and learning disabilities in mathematics are common.
3. Behavioral Symptoms
Behavioral symptoms are more extreme in males than in females and can include autism spectrum disorder, attention deficit disorder, and social anxiety. Males with this condition have a tendency to bite and flap their hands and to become aggressive. However, people often describe them as being kind and helpful and as having a good sense of humor.
Females sometimes share behavioral traits with males, but more commonly tend to express the syndrome through social anxiety, emotional disturbances, self-harm, and extreme shyness. Some females exhibit no behavioral symptoms.
4. Cause
Fragile X syndrome is the result of a mutation of the FMR1 gene, located on the X chromosome. This gene is normally responsible for making the fragile X mental retardation protein (FRMP). The body contains this protein in many locations, but it is especially abundant in the dendrites of neurons, where scientists believe it regulates the synthesis of other proteins.
A full mutation occurs in the FMR1 gene when a segment repeats over 200 times. This results in a non-functional gene that does not make a sufficient amount of FRMP and causes the symptoms of fragile X syndrome. A segment that repeats 50 to 200 times causes fragile X-associated tremor/ataxia syndrome or fragile X-associated primary ovarian insufficiency.
5. Associated Conditions
A less severe mutation of the FMR1 gene causes fragile X-associated tremor/ataxia syndrome (FXTAS). Sometimes children with this genetic problem experience learning disabilities, but most people do not realize they have it until age 50, when symptoms begin and then worsen over time. People experience hand tremors, problems with balance, and memory impairment.
Fragile X-associated primary ovarian insufficiency (FXPOI) describes another suite of symptoms associated with the lesser FMR1 mutation. The symptoms only affect women and include decreased fertility, hot flashes, and early menopause. However, women with FXPOI still release eggs and therefore may still become pregnant or have periods after not menstruating for several years.
6. Heritability
The mutation responsible for fragile X occurs on the X chromosome. Because women normally have two X chromosomes, they have a 50% chance of giving the mutation to each child. Men have only one X chromosome, so they have a 100% chance of passing it to their daughters and a 0% chance of passing it to their sons.
If a person’s FMR1 gene has the full mutation responsible for fragile X, a child will inherit the same mutation. A lesser form of the mutation also is inherited as-is, causing the associated syndromes of FXTAS and FXPOI. However, when inherited from the mother, the mutation can expand into its full form and cause fragile X.
7. Occurrence
One of 50 people worldwide have a slight mutation in the FMR1 gene that does not cause any problems. In the U.S., 1.5 million people carry the full mutation, with 100,000 of these exhibiting the symptoms of fragile X syndrome. Worldwide, fragile X syndrome occurs in approximately 1 in 3,600 to 4,000 males and 1 in 4,000 to 6,000 females.
Lesser forms of the mutation responsible for associated disorders are found in 1 in 468 males and 1 in 151 females worldwide. One study in Israel found 1 in 130 women to be carriers of the mutation. Twenty to 25% of these women have FXPOI, and 30 to 40% of men have FXTAS.
8. Diagnosis
Sometimes doctors may suspect fragile X syndrome based on a patient’s physical appearance, behavior, or other symptoms. Doctors recommend tests for these individuals, as well as for anyone with a family history of similar symptoms or known FMR1 mutations. Expectant mothers also may undergo genetic tests.
A 99% accurate test for the FMR1 mutation has been available since the 1990s. Patients supply blood or amniotic fluid for the test, which is accomplished using either Southern blot analysis or polymerase chain reaction analysis. It costs between $300 and $600 and can return results within one to four weeks.
9. Treatment
There is no cure for the fragile X syndrome mutation, but medications exist to ameliorate many symptoms. For example, stimulants, antidepressants, and mood stabilizers lessen the severity of behavioral symptoms such as ADHD, irritability, mania, obsessive-compulsive behavior, and anxiety.
There also is no cure for FXPOI. Symptoms such as hot flashes and irregular periods are improved by regulating the amount of estrogen in the body with hormone replacement therapy. Women experiencing FXPOI-related fertility issues can try assisted reproductive technologies like in vitro fertilization.
10. Clinical Trials and Research
Fragile X is the subject of research studies and clinical trials. At present, scientists are exploring the use of near-infrared spectroscopy and non-invasive EEGs as tools to better understand brain function of those with the condition. Others are testing the efficacy of new prescription medications.
One research study that has received considerable attention has used a combination of drugs to reactivate the FMR1 gene in isolated cells. Others are exploring gene-splicing technology. These or other techniques may one day lead to a cure for fragile X syndrome.
