Fragile X syndrome

Fragile X syndrome is a genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment. Usually, males are more severely affected by this disorder than females.

Males and females with fragile X syndrome may have anxiety and hyperactive behavior such as fidgeting or impulsive actions. They may also have attention deficit disorder (ADD), which includes an impaired ability to maintain attention and difficulty focusing on specific tasks. About one-third of males with fragile X syndrome also have features of autism spectrum disorders that affect communication and social interaction. Seizures occur in about 15 percent of males and about 5 percent of females with fragile X syndrome.

Many males with fragile X syndrome have characteristic physical features that become more apparent with age. These features include a long and narrow face, large ears, a prominent jaw and forehead, unusually flexible fingers, and enlarged testicles (macroorchidism) after puberty.

Fragile X syndrome occurs in approximately 1 in 4,000 males and 1 in 8,000 females.

Mutations in the FMR1 gene cause fragile X syndrome. The FMR1 gene provides instructions for making a protein called fragile X mental retardation 1 protein, whose function is not fully understood. This protein likely plays a role in the development of synapses, which are specialized connections between nerve cells. Synapses are critical for relaying nerve impulses.

Nearly all cases of fragile X syndrome are caused by a mutation in which a DNA segment, known as the CGG triplet repeat, is expanded within the FMR1 gene. 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 turns off (silences) the FMR1 gene, which prevents the gene from producing fragile X mental retardation 1 protein. Loss or a shortage (deficiency) of this protein disrupts nervous system functions and leads to the signs and symptoms of fragile X syndrome.

Males and females with 55 to 200 repeats of the CGG segment are said to have an FMR1 gene premutation. Most people with a premutation are intellectually normal. In some cases, however, individuals with a premutation have lower than normal amounts of the fragile X mental retardation 1 protein. As a result, they may have mild versions of the physical features seen in fragile X syndrome (such as prominent ears) and may experience emotional problems such as anxiety or depression. Some children with a premutation may have learning disabilities or autistic-like behavior. About 20 percent of women with a premutation have a condition called fragile X-associated primary ovarian insufficiency (FXPOI). These women may have irregular menstrual cycles, an inability to have children (infertility), early menopause, and elevated levels of a hormone known as follicle stimulating hormone (FSH). Men, and some women, with a premutation have an increased risk of developing a disorder known as fragile X-associated tremor/ataxia syndrome (FXTAS). This disorder is characterized by progressive problems with movement (ataxia), tremor, memory loss, loss of sensation in the lower extremities (peripheral neuropathy), and mental and behavioral changes.

Read more about the FMR1 gene.

Fragile X syndrome 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 Y chromosome is the other sex chromosome.) The inheritance is dominant if one copy of the altered gene in each cell is sufficient to cause the condition. X-linked dominant means that in females (who have two X chromosomes), a mutation in one of the two copies of a gene in each cell is sufficient to cause the disorder. In males (who have only one X chromosome), a mutation in the only copy of a gene in each cell causes the disorder. In most cases, males experience more severe symptoms of the disorder than females.

In women, the FMR1 gene premutation on the X chromosome can expand to more than 200 CGG repeats in cells that develop into eggs. This means that women with the premutation have an increased risk of having a child with fragile X syndrome. By contrast, the premutation in men does not expand to more than 200 repeats as it is passed to the next generation. Men pass the premutation only to their daughters. Their sons receive a Y chromosome, which does not include the FMR1 gene.