Fragile X syndrome, often called FXS, is the most common inherited form of intellectual disability. The condition was first described by two British scientists, the physician James Purdon Martin and the geneticist Julia Bell, in 1943. For many years, it was known as Martin-Bell syndrome. In 1969, Herbert Lubs, an American geneticist, discovered that the syndrome was associated with an unusual narrowing and occasional break at the end of the X chromosome, one of the two chromosomes that determine a person’s sex. The other is the Y chromosome. In 1991, scientists discovered the genetic mutation that causes FXS. A mutation is a permanent change in a gene’s coded chemical instructions.
FXS has a complicated pattern of inheritance, and the risk of a child having the disorder increases across generations of a family that possesses the mutation. The genetic mutation that causes FXS is known as a trinucleotide repeat expansion disorder. In FXS, a particular sequence of DNA on the X chromosome known as CGG, composed of the chemical compounds cytosine ( C ) and guanine ( G ), is greatly expanded beyond its normal size. This abnormal DNA sequence disrupts the production of a protein called fragile X mental retardation protein (FMRP) that is necessary for normal brain development.
Normally, the DNA sequence CGG is repeated between 5 and 50 times on the X chromosome. However, a trinucleotide repeat expansion disorder can cause the CGG sequence to repeat many more times, increase in length, and become unstable or fragile. Individuals who have from 50 to 200 repeats are called premutation carriers. These individuals can transmit FXS to their children but may not be affected themselves. Individuals with 200 or more CGG sequence repeats on the X chromosome will have the symptoms that characterize FXS.
Males have one X chromosome and one Y chromosome, and females have two X chromosomes. In general, males are more severely affected by FXS than females are because their only X chromosome carries the mutation. Males with FXS usually have mild to severe intellectual disability. They may also seem shy and have problems with social skills, anxiety, and attention. Many also speak rapidly and may repeat favorite words or topics. Some have autism, which is a condition characterized by limited ability to communicate and interact with other people. Females generally have milder symptoms because they often have a normal X chromosome to help counteract the effects of the abnormal one. Of affected females, about one-third will have normal development, one-third a mild learning disability, and one-third an intellectual disability. They may also be shy and have behavioral and emotional problems.
There is no cure for FXS. Physicians often prescribe medications to help behavioral and emotional problems. Individuals with FXS can also benefit from special education and therapy. Scientists are working to learn more about how FMRP works and what treatments can help restore or improve mental function. They are also investigating the use of gene therapy to treat this disorder (see Gene therapy). With a supportive family and school or work environment, most individuals with FXS can have a high quality of life despite the challenges they face.
See also Autism; Intellectual disability.
