Medical Genetics

Trinucleotide Repeats: Fragile-X Syndrome

What are trinucleotide repeats?

DNA, the chemical that makes up our genes, contains a "code" of three letter words known as "codons" or "trinucleotide repeats." Many genes normally contain a trinucleotide repeat which is present several times. When the number of trinucleotide repeats increases to a larger than normal number of copies, the DNA is altered, and the gene may not function properly, or may not work at all.

It is not well understood what causes a trinucleotide repeat to expand into more than the usual number of copies that should be in a gene. Sometimes, a person may have more than the usual number of copies, but not enough to alter the function of the gene. These individuals are referred to as "premutation carriers." When they pass on these extra copies to a child, however, the extra trinucleotide repeats cause the DNA to become unstable, and the area of DNA expands even more. The result is that the child has a gene that no longer functions, or is not functioning properly and they are said to have the "full mutation." An example of a trinucleotide repeat disease is Fragile-X syndrome.

What is Fragile-X syndrome?

Fragile-X syndrome causes moderate mental retardation in males and mild mental retardation in females. Symptoms of Fragile-X in childhood are not specific (they overlap with other disorders such as autism, Prader-Willi syndrome, and attention deficit-hyperactivity disorder, ADHD). Symptoms may include delays in development of speech, language, and motor skills. Autistic-like behavior and hyperactivity are also commonly seen with Fragile-X syndrome. Gaze aversion, or inability to make and hold eye contact, is very common among males and females with Fragile-X syndrome.

The gene for Fragile-X, called FMR-1, is located on the X chromosome. Females are usually not as severely affected as males because females have a normal X chromosome in addition to the X with the mutation. Also, females with the full syndrome are less common (about half the number of affected males) because they have two X chromosomes. The FMR-1 gene normally contains less than 44 trinucleotide repeats. Premutation carriers have about 59 to 200 trinucleotide repeats, and persons with Fragile-X syndrome have over 200 repeats.