Fragile X syndrome, the fragile X premutation, and the fragile X-associated tremor/ataxia syndrome (FXTAS) represent distinctly different ways in which the fragile X mental retardation 1 (FMR1) gene is expressed. FMR1 is a gene located on the X chromosome, one of two chromosomes that determine a person's sex. (For this reason, these disorders are described as "X-linked.") In each of these conditions, there is a mutation of the genetic material that makes up the FMR1 gene. The mutation involves an expansion in a region of the gene that typically contains about 29 or 30 repetitions of a specific pattern of molecules (i.e., cytosine, guanine, and guanine, or "CGG") The number of repetitions of the pattern is referred to as "CGG repeats." If a person has 6 CGG repeats, the sequence of these molecules in his/her DNA would be CGG CGG CGG CGG CGG CGG. Individuals with between 6 and 40 repetitions of the CGG pattern are considered to have a normal gene. Those with more that 200 CGG repeats have the "full mutation," which causes fragile X syndrome, the most severe of the conditions known to be associated with the FMR1 gene.
Some individuals have an expansion of the CGG pattern that is less severe than the expansion seen in the full mutation. Men and women with expansions in the range of 55 to 200 CGG repeats have what is called the fragile X premutation. These individuals are referred to as "carriers" of the mutated gene, as they may transmit either the full mutation or the premutation to their children. Individuals in the premutation range typically are normal in their appearance and functioning. Even those who are mildly affected experience significantly less severe symptoms than are typically seen in individuals with the full mutation. A proportion of individuals with the premutation (probably at least one-third) develop FXTAS, a progressive movement disorder, later in life.
Men and women with CGG repeats in the range of 41 to 54 are referred to as being in the intermediate or "gray" zone. Although this group has not been studied thoroughly, it is believed that men and women with CGG repeat expansions in this range experience no ill effects related to the mutated gene. However, it may be possible for these individuals to pass the premutation of the FMR1 gene to their children.
There are two chromosomes (X and Y) that, in combination, determine the sex of an individual. Women have two X chromosomes, whereas men have one X chromosome and one Y chromosome. During reproduction, a child receives one sex chromosome from each parent. A mother contributes a copy of one of her X chromosomes. A father contributes a copy of either his X chromosome or his Y chromosome. If the father provides his X chromosome, the child will be female. If the father provides his Y chromosome, the child will be male. Because the FMR1 gene is located on the X chromosome, the inheritance of a mutated gene differs depending on the sex of the affected parent and the sex of the child.
The following diagram depicts the genetic inheritance of the FMR1 gene. The left side of the diagram represents the transmission of a mutated gene (either the full mutation or the premutation) from an affected father to his children. A father always provides a copy of his Y chromosome to his sons. Because the fragile X gene is located on the X chromosome, which the father does not transmit to his sons, it is impossible for a man to pass on a mutated FMR1 gene to his male child. Because he has only one X chromosome, which he provides to each of his female children, an affected father will pass on the mutated gene to all of his daughters.
The right side of the diagram depicts the transmission of a mutated FMR1 gene from a mother to her children. Because she has two X chromosomes, an affected woman will pass either the X chromosome containing the mutated gene or her other X chromosome (which is likely to contain a normal gene) to each of her children. Each child has a 50% chance of receiving the mutated gene. The likelihood of receiving the X chromosome containing the mutated gene does not differ for male and female children of an affected mother.
A mutation in the FMR1 gene can increase in severity across generations. That is, the gene can undergo further expansion (i.e., the number of CGG repeats increases) as it is passed from parent to child. Expansion in the size of the genetic mutation tends to occur during the development of the egg cells of a woman who carries the premutation. Hence, a woman with the premutation often will pass a larger premutation or the full mutation on to her children. The larger the mother's FMR1 repeat expansion, the more likely she is to pass on the full mutation (women with more than 80 CGG repeats are particularly at risk). A mutated FMR1 gene passed from an affected father to his daughter generally remains roughly the same size across the two generations. That is, if the father carries the premutation, his daughter is likely to carry the premutation (rather than the full mutation).