Fragile X syndrome is the most common genetically-inherited form of mental retardation currently known. In addition to intellectual disability, some individuals with Fragile X display common physical traits and characteristic facial features, such as prominent ears. Children with Fragile X often appear normal in infancy but develop typical physical characteristics during their lifetime. Mental impairment may range from mild learning disability and hyperactivity to severe mental retardation and autism. This genetic syndrome is caused by a defect on the X chromosome. Because of scientific advances, improvements in genetic testing, and increased awareness, the number of children diagnosed with Fragile X has increased significantly over the last decade.

A substantial research effort led to the 1991 discovery of FMR-1 (Fragile X mental retardation), the gene that when damaged causes Fragile X. Although the normal function of the FMR-1 gene is not fully understood, it appears to be important early in development. The mechanism by which the normal FMR-1 gene is converted into an altered, or mutant, gene capable of causing disease symptoms involves an increase in the length of the gene. A small region of the gene, CGG, undergoes repeated duplications, forming deoxyribonucleic acid (DNA) repeats that result in a longer gene. The lengthened DNA region is susceptible to a chemical modification process called DNA methylation. When the number of repeats is small (less than 200) the individual often has no signs of the disorder. However, in individuals with a larger number of repeats, the characteristics that are typical of Fragile X are observed. In families that exhibit Fragile X, both the number of repeats and the length of the chromosome increase with succeeding generations. The severity of the symptoms increases with the increasing length of the repeated region.

Fragile X exhibits X-linkage. The effect of X-linkage is that the frequency of the syndrome is greater in males than in females. To understand the mechanism of X-linkage some background information on the organization of human chromosomes is needed. Human females typically have two X chromosomes, and human males have one X and one Y chromosome. A female who inherits a chromosome carrying the Fragile X gene from either parent is likely to inherit a normal X chromosome from the other parent. The normal X chromosome could provide the normal gene function and mask the presence of the Fragile X gene in a female. In that case, the female would still possess the Fragile X gene and be capable of passing it on to her offspring, but she would not exhibit symptoms. She would be a "carrier." On the other hand, a male who inherits the Fragile X gene from his mother would inherit a Y chromosome and not a normal X chromosome from his father, and therefore a male with one copy of the gene is likely to show symptoms. We do not yet have a complete understanding of the mechanism of genetic transmission of Fragile X. For example, it is not known why approximately one-fifth of males who carry mutated forms of FMR-1 are either unaffected or only mildly affected. In some cases, a single copy of the Fragile X gene is sufficient to cause the syndrome in females. The situation is made more complex by the fact that the intensity of the symptoms increases with succeeding generations. The observable characteristics of Fragile X occur in approximately 1 in 1,000 male births and 1 in 2,500 female births.

On a normal X chromosome, the FMR-1 region of the chromosome contains 50 or fewer copies of the CGG repeat. This same region may be repeated hundreds or even thousands of times in individuals with Fragile X. Researchers have made a surprising correlation between the number of DNA repeats and the degree of clinical impairment. Individuals with between 50 and 200 repeats are often carriers of Fragile X who have mild symptoms or no symptoms at all. When the number of repeats increases, the chemical modification process called DNA methylation is more likely to occur. It is this chemical modification that appears to inactivate the FMR-1 gene, leading to deficits in cognitive processing. Why methylation of this region of DNA leads to the symptoms of Fragile X is not understood. Mental impairment in Fragile X appears to correlate with DNA containing more than 200 repeats. In that case, most males are impaired and 50 percent of females show some learning disabilities. However, there are exceptions, including individuals with enormous numbers of repeats who have no apparent impairment.

Inheritance

In normal individuals the FMR-1 gene is passed on, in stable fashion, from the parent to the offspring. In Fragile X individuals, the repeated sequences not only expand abnormally, but are unstable and the degree of impairment in offspring may vary. The Fragile X mutation appears to increase in length as it is inherited by succeeding generations. This phenomenon is known as "genetic anticipation." Eventually, the mutation reaches a critical number of repeats and causes Fragile X syndrome. For example, a male may have normal IQ, no Fragile X symptoms, and a short region of DNA repeats at the Fragile X region of his X chromosome. This individual, called a "transmitting" male, may have a daughter with 50 to 200 repeats. At that stage the condition is considered a "premutation," as there still may be no apparent symptoms. This daughter, a "carrier," might have a son with 1,000 repeats and the full blown Fragile X syndrome. If a woman is a carrier, each of her children has a 50 percent chance of inheriting her Fragile X gene. Each time her Fragile X gene is inherited, it is likely to have expanded in length. A daughter who inherits the gene will be a carrier with some chance of impairment; a son who inherits the gene has an 80 percent likelihood of developing Fragile X syndrome.

Testing for Fragile X Carrier

A simple test is now available that can determine if a woman is carrier of the Fragile X gene. A drop of blood can be taken from the woman's finger and analyzed quickly and inexpensively. If a woman who is found to be a carrier is pregnant, she can arrange for testing of the fetus, as described below. For a woman with a family history of retardation, testing before pregnancy will help determine if she is at risk.