About Fragile X Syndrome

Fragile X syndrome is the most common form of inherited intellectual disability in males and is also a significant cause of intellectual disability in females. It affects about 1 in 4,000 males and 1 in 8,000 females and occurs in all racial and ethnic groups.

Nearly all cases of fragile X syndrome are caused by an alteration (mutation) in the FMR1 gene where a DNA segment, known as the CGG triplet repeat, is expanded. Normally, this DNA segment is repeated from 5 to about 40 times. In people with fragile X syndrome, however, the CGG segment is repeated more than 200 times. The abnormally expanded CGG segment inactivates (silences) the FMR1 gene, which prevents the gene from producing a protein called fragile X mental disability protein. Loss of this protein leads to the signs and symptoms of fragile X syndrome. Both boys and girls can be affected, but because boys have only one X chromosome, a single fragile X is likely to affect them more severely.

A boy who has the full FMR1 mutation has fragile X syndrome and will have moderate intellectual disability. They have a particular facial appearance, characterized by a large head size, a long face, prominent forehead and chin and protruding ears. In addition males who have fragile X syndrome have loose joints (joint laxity), and large testes (after puberty).

Affected boys may have behavioral problems such as hyperactivity, hand flapping, hand biting, temper tantrums and autism. Other behaviors in boys after they have reached puberty include poor eye contact, perseverative speech, problems in impulse control and distractibility. Physical problems that have been seen include eye, orthopedic, heart and skin problems.

Girls who have the full FMR1 mutation have mild intellectual disability.

Family members who have fewer repeats in the FMR1 gene may not have intellectual disability, but may have other problems. Women with less severe changes may have premature menopause or difficulty becoming pregnant.

Both men and women may have problems with tremors and poor coordination.

People with about 55 to 200 repeats of the CGG segment are said to have an FMR1 premutation (an intermediate variation of the gene). In women, the premutation is liable to expand to more than 200 repeats in cells that develop into eggs. This means that women with the FMR1 premutation have an increased risk of having a child with fragile X syndrome. By contrast, the premutation CGG repeat in men remains at the same size or shortens as it is passed to the next generation.

Males and females who have a fragile X premutation have normal intellect and appearance. A few individuals with a premutation have subtle intellectual or behavioral symptoms, such as learning difficulties or social anxiety. The difficulties are usually not socially debilitating, and these individuals may still marry and have children.

Males who have a premutation with 59 to 200 CGG trinucleotide repeats are usually unaffected and are at risk for fragile X-associated tremor/ataxia syndrome (FXTAS). The fragile X-associated tremor/ataxia syndrome (FXTAS) is characterized by late-onset, progressive cerebellar ataxia and intention tremor in males who have a premutation. Other neurologic findings include short-term memory loss, executive function deficits, cognitive decline, parkinsonism, peripheral neuropathy, lower-limb proximal muscle weakness, and autonomic dysfunction.

The degree to which clinical symptoms of fragile X are present (penetrance) is age related; symptoms are seen in 17 percent of males aged 50-59 years, in 38 percent of males aged 60-69 years, in 47 percent of males aged 70-79 years, and in 75 percent or males aged 80 years or older. Some female premutation carriers may also develop tremor and ataxia.

Females who have a premutation usually are unaffected, but may be at risk for premature ovarian failure and FXTAS. Premature ovarian failure (POF) is defined as cessation of menses before age 40 years, has been observed in carriers of premutation alleles. A review by Sherman (2005) concluded that the risk for POF was 21 percent in premutation carriers compared to a 1 percent for the general population.

There are very few outward signs of fragile X syndrome in babies, but one is a tendency to have a large head circumference. An experienced geneticist may note subtle differences in facial characteristics. Intellectual disability is the hallmark of this condition and, in females, this may be the only sign of the problem.

A specific genetic test (polymerase chain reaction [PCR]) can now be performed to diagnose fragile X syndrome. This test looks for an expanded mutation (called a triplet repeat) in the FMR1 gene.

There is no specific treatment available for fragile X syndrome. Supportive therapy for children who have fragile X syndrome includes:

• Special education and anticipatory management including avoidance of excessive stimulation to decrease behavioral problems.

• Medication to manage behavioral issues, although no specific medication has been shown to be beneficial.

• Early intervention, special education and vocational training.

• Vision, hearing, connective tissue problems, and heart problems when present are treated in the usual manner.

This condition is inherited in an X-linked dominant pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. The inheritance is dominant if one copy of the altered gene in each cell is sufficient to cause the condition. In most cases, males experience more severe symptoms of the disorder than females. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.