Fragile X syndrome Health Article

Definition

Fragile X syndrome is the most common form of inherited mental retardation. Individuals with this condition have developmental delay, variable levels of mental retardation, and behavioral and emotional difficulties. They may also have characteristic physical traits. Generally, males are affected with moderate mental retardation and females with mild mental retardation.

Description

Fragile X syndrome is also known as Martin-Bell syndrome, Marker X syndrome, and FRAXA syndrome. It is the most common form of inherited mental retardation. Fragile X syndrome is caused by a mutation in the FMR-1 gene, located on the X chromosome. The role of the gene is unclear, but it is probably important in early development.

Genetic profile

In order to understand fragile X syndrome it is important to understand how human genes and chromosomes influence this condition. Normally, each cell in the body contains 46 (23 pairs of) chromosomes. These chromosomes consist of genetic material (DNA) needed for the production of proteins, which lead to growth, development, and physical/intellectual characteristics. The first 22 pairs of chromosomes are the same in males and females. The remaining two chromosomes are called the sex chromosomes (X and Y). The sex chromosomes determine whether a person is male or female. Males have only one X chromosome, which is inherited from the mother at conception, and they receive a Y chromosome from the father. Females inherit two X chromosomes, one from each parent. Fragile X syndrome is caused by a mutation in a gene called FMR-1. This gene is located on the X chromosome. The FMR-1 gene is thought to play an important role in the development of the brain, but the exact way that the gene acts in the body is not fully understood.

The mutation involves a short sequence of DNA in the FMR-1 gene. This sequence is designated CGG. Normally, the CGG sequence is repeated between six and 54 times. People who have repeats in this range do not have fragile X syndrome and are not at increased risk to have children with fragile X syndrome. Those affected by fragile X syndrome have expanded CGG repeats (over 200) in the first exon of the FMR1 gene (the full mutation).

For reasons not fully understood, the CGG sequence in the FMR-1 gene can expand to contain between 54 and 230 repeats. This stage of expansion is called a premutation. People who carry a premutation do not usually have symptoms of fragile X syndrome; although there have been reports of individuals with a premutation and subtle intellectual or behavioral symptoms. Individuals who carry a fragile X premutation are at risk to have children or grandchildren with the condition. Female premutation carriers may also be at increased risk for earlier onset of menopause; however, premutation carriers may exist through several generations of a family and no symptoms of fragile X syndrome will appear.

The size of the premutation can expand over succeeding generations. Once the size of the premutation exceeds 230 repeats, it becomes a full mutation and the FMR-1 gene is disabled. Individuals who carry the full mutation may have fragile X syndrome. Since the FMR-1 gene is located on the X chromosome, males are more likely to develop symptoms than females. This is because males have only one copy of the X chromosome. Males who inherit the full mutation are expected to have mental impairment. A female's normal X chromosome may compensate for her chromosome with the fragile X gene mutation. Females who inherit the full mutation have an approximately 50% risk of mental impairment. The phenomenon of an expanding trinucleotide repeat in successive generations is called anticipation. Another unique aspect fragile X syndrome is that mosaicism is present in 15-20% those affected by the condition. Mosaicism is when there is the presence of cells of two different genetic materials in the same individual.

Fragile X syndrome is inherited in an X-linked dominant manner (characters are transmitted by genes on the X chromosome). When a man carries a premutation on his X chromosome, it tends to be stable and usually will not expand if he passes it on to his daughters (he passes his Y chromosome to his sons). Thus, all of his daughters will be premutation carriers like he is. When a woman carries a premutation, it is unstable and can expand as she passes it on to her children; therefore, her grandchildren are at greater risk of developing the syndrome. There is a 50% risk for a premutation carrier female to transmit an abnormal mutation with each pregnancy. The likelihood for the premutation to expand is related to the number of repeats present; the higher the number of repeats, the greater the chance that the premutation will expand to a full mutation in the next generation. All mothers of a child with a full mutation are carriers of an FMR-1 gene expansion. Ninety-nine percent of patients with fragile X syndrome have a CGG expansion, and less than one percent have a point mutation or deletion on the FMR-1 gene.